((Title))
Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1)Clare F. Megarity[a],-298457442200[a]Dr Clare F. Megarity, Dr Mary Clare Caraher, Dr David J. Timson, School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK[b]Dr Hoda Abdel-Aal Bettley, Dr M. Clare Caraher, Dr Katherine Scott, Dr Richard A. Bryce, Dr Karen A. Nolan, Prof Ian J. Stratford, Manchester Pharmacy School, [c] Dr Roger C. Whitehead, School of Chemistry, and [d] DrThomas A. Jowitt, The Faculty of Life Science, Manchester Cancer Research Centre and the University of Manchester, Oxford Road, Manchester, M13 9PT, UK[e]Dr Aldo Gutierrez, Department of Biosciences, Nottingham Trent University, Nottingham NG1 4BU, UK[f]Prof David J Timson, School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK; +44(0)1273 641623; d.timson@brighton.ac.ukSupporting information for this article is given via a link at the end of the document.00[a]Dr Clare F. Megarity, Dr Mary Clare Caraher, Dr David J. Timson, School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK[b]Dr Hoda Abdel-Aal Bettley, Dr M. Clare Caraher, Dr Katherine Scott, Dr Richard A. Bryce, Dr Karen A. Nolan, Prof Ian J. Stratford, Manchester Pharmacy School, [c] Dr Roger C. Whitehead, School of Chemistry, and [d] DrThomas A. Jowitt, The Faculty of Life Science, Manchester Cancer Research Centre and the University of Manchester, Oxford Road, Manchester, M13 9PT, UK[e]Dr Aldo Gutierrez, Department of Biosciences, Nottingham Trent University, Nottingham NG1 4BU, UK[f]Prof David J Timson, School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK; +44(0)1273 641623; d.timson@brighton.ac.ukSupporting information for this article is given via a link at the end of the document.Hoda Abdel-Aal Bettley[b], M. Clare Caraher[a],[b], Katherine A. Scott[b], Roger C. Whitehead[c], Thomas A. Jowitt[d], Aldo Gutierrez[e], Richard A. Bryce[b], Karen A. Nolan[b], Ian J. Stratford[b], David J. Timson*[a],[f]Abstract: NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone/nanny protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing co-factor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion may contribute to the biological effects of putative inhibitors of NQO1.IntroductionNAD(P)H quinone oxidoreductase (NQO1, DT-diaphorase, E.C. 1.6.5.2) is a homodimeric flavoprotein with one molecule of non-covalently bound flavin adenine dinucleotide (FAD) per monomer.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA [1a] NQO1 is a detoxification enzyme with its main function being the obligate two-electron reduction of quinones to hydroquinones. ADDIN EN.CITE <EndNote><Cite><Author>Lind</Author><Year>1982</Year><RecNum>2965</RecNum><DisplayText><style face="superscript">[2]</style></DisplayText><record><rec-number>2965</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">2965</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lind, C.</author><author>Hochstein, P.</author><author>Ernster, L.</author></authors></contributors><titles><title>DT-diaphorase as a quinone reductase: a cellular control device against semiquinone and superoxide radical formation</title><secondary-title>Archives of Biochemistry and Biophysics</secondary-title></titles><periodical><full-title>Archives of Biochemistry and Biophysics</full-title></periodical><pages>178-185</pages><volume>216</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Benzoquinones</keyword><keyword>Cytosol/metabolism</keyword><keyword>Kinetics</keyword><keyword>Liver/metabolism</keyword><keyword>Male</keyword><keyword>Microsomes, Liver/enzymology</keyword><keyword>NADH, NADPH Oxidoreductases/metabolism</keyword><keyword>NADP/metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxygen Consumption</keyword><keyword>Quinone Reductases/metabolism</keyword><keyword>Quinones</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword><keyword>Superoxides</keyword></keywords><dates><year>1982</year></dates><pub-location>UNITED STATES</pub-location><isbn>0003-9861; 0003-9861</isbn><urls></urls><electronic-resource-num>0003-9861(82)90202-8 [pii]</electronic-resource-num><access-date>Jun</access-date></record></Cite></EndNote>[2] The enzyme is unusual in that it can use either NADH or NADPH in the first step of its catalytic process, the transfer of a hydride group to the FAD molecule.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA [1a, 3] The second step is the transfer of the hydride group from the reduced cofactor to the newly docked quinone substrate, but this can only occur once the NAD(P)+ has been released, hence the description of the mechanism as a “ping-pong” reaction.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA [1a]. However, in an early study of NQO1 from rat liver, enzyme kinetic analysis indicated non-equivalent active sites and negative cooperativity towards some inhibitors. ADDIN EN.CITE <EndNote><Cite><Author>Rase</Author><Year>1976</Year><RecNum>4167</RecNum><DisplayText><style face="superscript">[5]</style></DisplayText><record><rec-number>4167</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rase, B.</author><author>Bartfai, T.</author><author>Ernster, L.</author></authors></contributors><titles><title>Purification of DT-diaphorase by affinity chromatography. Occurrence of two subunits and nonlinear Dixon and Scatchard plots of the inhibition by anticoagulants</title><secondary-title>Archives of Biochemistry and Biophysics</secondary-title></titles><periodical><full-title>Archives of Biochemistry and Biophysics</full-title></periodical><pages>380-386</pages><volume>172</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Binding Sites</keyword><keyword>Chromatography, Affinity</keyword><keyword>Dicumarol</keyword><keyword>Kinetics</keyword><keyword>Liver/enzymology</keyword><keyword>Male</keyword><keyword>Molecular Weight</keyword><keyword>NADH, NADPH Oxidoreductases/isolation & purification</keyword><keyword>Protein Binding</keyword><keyword>Quinone Reductases/antagonists & inhibitors/isolation & purification/metabolism</keyword><keyword>Rats</keyword><keyword>Warfarin</keyword></keywords><dates><year>1976</year></dates><pub-location>UNITED STATES</pub-location><isbn>0003-9861; 0003-9861</isbn><urls></urls><access-date>Feb</access-date></record></Cite></EndNote>[5] Recent work combining biophysical and computational methods has demonstrated considerable effects of mobility within the enzyme. Although the C-terminal domain (CTD) is not directly involved in forming the active site, removal of this part of the protein dramatically reduces the affinity for FAD and, consequently, catalytic activity.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWRpbmEtQ2FybW9uYTwvQXV0aG9yPjxZZWFyPjIwMTY8
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ADDIN EN.CITE.DATA [7] This negative cooperativity of cofactor binding may have implications for catalysis and the binding of other ligands ADDIN EN.CITE <EndNote><Cite><Author>Pey</Author><Year>2019</Year><RecNum>7205</RecNum><DisplayText><style face="superscript">[8]</style></DisplayText><record><rec-number>7205</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1554822028">7205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pey, A. L.</author><author>Megarity, C. F.</author><author>Timson, D. J.</author></authors></contributors><auth-address>Department of Physical Chemistry, Faculty of Sciences, University of Granada, Av. Fuentenueva s/n, Granada 18071, Spain.
Medical Biology Centre, School of Biological Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K.
School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton BN2 4GJ, U.K. d.timson@brighton.ac.uk.</auth-address><titles><title>NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places</title><secondary-title>Biosci Rep</secondary-title><alt-title>Bioscience reports</alt-title></titles><periodical><full-title>Biosci Rep</full-title></periodical><alt-periodical><full-title>Bioscience Reports</full-title></alt-periodical><pages>BSR20180459</pages><volume>39</volume><number>1</number><edition>2018/12/07</edition><section>BSR20180459</section><keywords><keyword>*DT-diaphorase</keyword><keyword>*cancer-associated mutation</keyword><keyword>*negative cooperativity</keyword><keyword>*protein mobility</keyword><keyword>*quinone oxidoreductase</keyword></keywords><dates><year>2019</year><pub-dates><date>Jan 31</date></pub-dates></dates><isbn>0144-8463</isbn><accession-num>30518535</accession-num><urls></urls><custom2>PMC6328894</custom2><electronic-resource-num>10.1042/bsr20180459</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[8].NQO1 has also been shown to have chaperone properties. It stabilises the tumour suppressor protein p53 and other short-lived proteins such as p73α and ornithine decarboxylase.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2hlcjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [9] This stabilization phenomenon is NAD(P)H-dependent and inhibitors of NQO1, such as dicoumarol and curcumin, which compete with NAD(P)H, have been shown to promote p53 degradation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2hlcjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [13] Consequently a number of studies have focussed on identifying novel inhibitors of NQO1, often ones which are structurally similar to dicoumarol 1 (Scheme 1) or quinones, for example see reference PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob2xhbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [14]. Conversely, reduced NQO1 activity resulting from polymorphic forms of NQO1, the most common of which results in a proline to serine substitution at position 187, can result in genetic predisposition to certain types of cancer, presumably due to reduced cellular antioxidant activity. ADDIN EN.CITE <EndNote><Cite><Author>Lajin</Author><Year>2013</Year><RecNum>2734</RecNum><DisplayText><style face="superscript">[15]</style></DisplayText><record><rec-number>2734</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">2734</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lajin, B.</author><author>Alachkar, A.</author></authors></contributors><auth-address>Department of Analytical Chemistry, Faculty of Pharmacy, University of Aleppo, Aleppo, Syria. BassamL7@yahoo.co.uk</auth-address><titles><title>The NQO1 polymorphism C609T (Pro187Ser) and cancer susceptibility: a comprehensive meta-analysis</title><secondary-title>British journal of cancer</secondary-title></titles><periodical><full-title>British journal of cancer</full-title></periodical><pages>1325-1337</pages><volume>109</volume><number>5</number><keywords><keyword>Female</keyword><keyword>Genetic Association Studies</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/genetics</keyword><keyword>Neoplasms/enzymology/genetics</keyword><keyword>Polymorphism, Single Nucleotide</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2013</year></dates><pub-location>England</pub-location><isbn>1532-1827; 0007-0920</isbn><urls></urls><electronic-resource-num>10.1038/bjc.2013.357 [doi]</electronic-resource-num><access-date>Sep 3</access-date></record></Cite></EndNote>[15] This P187S variant has reduced affinity for FAD and increased susceptibility to proteolytic degradation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [6a, 6b, 16]The importance of NQO1 in detoxification, molecular pathology and as a potential drug target all mean that understanding the enzyme’s interaction with ligands is critical. The potential for cooperativity in the enzyme suggests communication between the active sites. These phenomena are likely to have effects beyond enzymology and may impact on NQO1’s cellular roles as a chaperone. Here, we demonstrate kinetic negative cooperativity of human NQO1 by dicoumarol and three structurally related inhibitors (compounds 1-4; Scheme 1). Overall, our results paint a picture of an enzyme in which modulation of protein motions mediates communication between the two active sites.Scheme 1: The compounds used in this study. All four of these compounds have been shown to inhibit NQO1 in vitro and the growth of HT29 cells in culture. IC50 values have been reported previously.14 Compound 1 is dicoumarol. Compounds 2, 3 and 4 were designated AS1, AS3 and S4 in previous work.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob2xhbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [14a, 14c]Results and DiscussionCellular inhibition of NQO1 results in lower p53 levelsPrevious studies have shown that dicoumarol (1) inhibits NQO1 in vivo and, consequently, reduces the amount of the apoptosis regulator p53.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2hlcjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [14a, 14c] Thus, these newly identified inhibitors have promise for the pharmacological inhibition of NQO1 and associated reduction in p53 levels with reduced side-effects compared to 1.Human NQO1 shows negative cooperativity towards inhibitors, but not towards NAD(P)HIn the 1970s, it was reported that rat NQO1 shows negative cooperativity towards some inhibitors, including 1. ADDIN EN.CITE <EndNote><Cite><Author>Rase</Author><Year>1976</Year><RecNum>4167</RecNum><DisplayText><style face="superscript">[5]</style></DisplayText><record><rec-number>4167</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rase, B.</author><author>Bartfai, T.</author><author>Ernster, L.</author></authors></contributors><titles><title>Purification of DT-diaphorase by affinity chromatography. Occurrence of two subunits and nonlinear Dixon and Scatchard plots of the inhibition by anticoagulants</title><secondary-title>Archives of Biochemistry and Biophysics</secondary-title></titles><periodical><full-title>Archives of Biochemistry and Biophysics</full-title></periodical><pages>380-386</pages><volume>172</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Binding Sites</keyword><keyword>Chromatography, Affinity</keyword><keyword>Dicumarol</keyword><keyword>Kinetics</keyword><keyword>Liver/enzymology</keyword><keyword>Male</keyword><keyword>Molecular Weight</keyword><keyword>NADH, NADPH Oxidoreductases/isolation & purification</keyword><keyword>Protein Binding</keyword><keyword>Quinone Reductases/antagonists & inhibitors/isolation & purification/metabolism</keyword><keyword>Rats</keyword><keyword>Warfarin</keyword></keywords><dates><year>1976</year></dates><pub-location>UNITED STATES</pub-location><isbn>0003-9861; 0003-9861</isbn><urls></urls><access-date>Feb</access-date></record></Cite></EndNote>[5] More recently, negative cooperativity towards inhibitors has been observed in the functionally related proteins human NRH quinone oxidoreductase 2 (NQO2; EC 1.10.5.1) and Saccharomyces cerevisiae Lot6p (EC 1.5.1.39).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWdhcml0eTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA [14a, 19] (Table 1; Figure S4). Negative cooperativity towards 1-4 was confirmed by direct binding experiments using isothermal titration calorimetry. The binding of ligands to the dimeric NQO1 was best fitted to a “sequential binding sites” model (Figure S5).Negative cooperativity in NQO1 can be disrupted by a single amino acid substitutionNegative cooperativity implies that there is some form of communication between the active sites. This can be mediated by conformational changes or through alterations in the mobility of elements of the protein’s structure. ADDIN EN.CITE <EndNote><Cite><Author>Goodey</Author><Year>2008</Year><RecNum>1708</RecNum><DisplayText><style face="superscript">[20]</style></DisplayText><record><rec-number>1708</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">1708</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goodey, N. M.</author><author>Benkovic, S. J.</author></authors></contributors><auth-address>Montclair State University, Department of Chemistry and Biochemistry, 1 Normal Avenue, Montclair, New Jersey 07043, USA.</auth-address><titles><title>Allosteric regulation and catalysis emerge via a common route</title><secondary-title>Nature chemical biology</secondary-title></titles><periodical><full-title>Nature chemical biology</full-title></periodical><pages>474-482</pages><volume>4</volume><number>8</number><keywords><keyword>Allosteric Regulation</keyword><keyword>Catalysis</keyword><keyword>Protein Conformation</keyword><keyword>Proteins/chemistry/metabolism</keyword></keywords><dates><year>2008</year></dates><pub-location>United States</pub-location><isbn>1552-4469; 1552-4450</isbn><urls></urls><electronic-resource-num>10.1038/nchembio.98</electronic-resource-num><access-date>Aug</access-date></record></Cite></EndNote>[20] Since glycine residues permit the greatest flexibility of a polypeptide chain, we concentrated on these residues as possible places to disrupt communication between the active sites. ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>2003</Year><RecNum>2109</RecNum><DisplayText><style face="superscript">[21]</style></DisplayText><record><rec-number>2109</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">2109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, F.</author><author>Nau, W. M.</author></authors></contributors><auth-address>Departement Chemie, Universitat Basel, Klingelbergstrasse 80, 4056 Basel, Switzerland.</auth-address><titles><title>A conformational flexibility scale for amino acids in peptides</title><secondary-title>Angewandte Chemie (International ed.in English)</secondary-title></titles><periodical><full-title>Angewandte Chemie (International ed.in English)</full-title></periodical><pages>2269-2272</pages><volume>42</volume><number>20</number><keywords><keyword>Amino Acids/chemistry/metabolism</keyword><keyword>Deuterium/metabolism</keyword><keyword>Molecular Structure</keyword><keyword>Peptides/chemistry/metabolism</keyword><keyword>Protein Conformation</keyword></keywords><dates><year>2003</year></dates><pub-location>Germany</pub-location><isbn>1433-7851; 1433-7851</isbn><urls></urls><electronic-resource-num>10.1002/anie.200250684 [doi]</electronic-resource-num><access-date>May 25</access-date></record></Cite></EndNote>[21] We focussed on three residues, Gly149, Gly150 and Gly174. These amino acids are in proximity to the dicoumarol binding site and Gly174 breaks α-helix α4 (following the notation of Faig et al.) ADDIN EN.CITE <EndNote><Cite><Author>Faig</Author><Year>2001</Year><RecNum>1330</RecNum><DisplayText><style face="superscript">[14g]</style></DisplayText><record><rec-number>1330</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">1330</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Faig, M.</author><author>Bianchet, M. A.</author><author>Winski, S.</author><author>Hargreaves, R.</author><author>Moody, C. J.</author><author>Hudnott, A. R.</author><author>Ross, D.</author><author>Amzel, L. M.</author></authors></contributors><auth-address>Department of Biophysics and Biophysical Chemistry, Johns Hopkins Medical School, Baltimore, MD 21205, USA.</auth-address><titles><title>Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones</title><secondary-title>Structure (London, England : 1993)</secondary-title></titles><periodical><full-title>Structure (London, England : 1993)</full-title></periodical><pages>659-667</pages><volume>9</volume><number>8</number><keywords><keyword>Antineoplastic Agents/chemistry/pharmacology</keyword><keyword>Benzoquinones/chemistry</keyword><keyword>Binding Sites</keyword><keyword>Catalytic Domain</keyword><keyword>Crystallography, X-Ray</keyword><keyword>Drug Design</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Models, Chemical</keyword><keyword>Protein Binding</keyword><keyword>Quinone Reductases/chemistry</keyword><keyword>Quinones/chemistry/therapeutic use</keyword><keyword>Recombinant Proteins/chemistry</keyword></keywords><dates><year>2001</year></dates><pub-location>United States</pub-location><isbn>0969-2126; 0969-2126</isbn><urls></urls><electronic-resource-num>S0969212601006360 [pii]</electronic-resource-num><access-date>Aug</access-date></record></Cite></EndNote>[14g] which spans the distance between the active sites (residues 163-180). ADDIN EN.CITE <EndNote><Cite><Author>Asher</Author><Year>2006</Year><RecNum>173</RecNum><DisplayText><style face="superscript">[22]</style></DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asher, G.</author><author>Dym, O.</author><author>Tsvetkov, P.</author><author>Adler, J.</author><author>Shaul, Y.</author></authors></contributors><auth-address>Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.</auth-address><titles><title>The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol</title><secondary-title>Biochemistry</secondary-title></titles><periodical><full-title>Biochemistry</full-title></periodical><pages>6372-6378</pages><volume>45</volume><number>20</number><keywords><keyword>Animals</keyword><keyword>Apoproteins/metabolism</keyword><keyword>Benzoquinones/chemistry/metabolism</keyword><keyword>Catalytic Domain</keyword><keyword>Crystallization</keyword><keyword>Crystallography, X-Ray</keyword><keyword>Dicumarol/chemistry/metabolism</keyword><keyword>Enzyme Inhibitors/chemistry/metabolism</keyword><keyword>Humans</keyword><keyword>Indolequinones/chemistry/metabolism</keyword><keyword>Models, Molecular</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/chemistry/metabolism</keyword><keyword>Phenylalanine/metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Rats</keyword><keyword>Triazines/chemistry/metabolism</keyword><keyword>Tyrosine/metabolism</keyword></keywords><dates><year>2006</year></dates><pub-location>United States</pub-location><isbn>0006-2960; 0006-2960</isbn><urls></urls><electronic-resource-num>10.1021/bi0600087 [doi]</electronic-resource-num><access-date>May 23</access-date></record></Cite></EndNote>[22]Alteration of Gly149 to serine resulted in no change in the Hill coefficient for ligand 1. When Gly174 was changed to serine, the purified protein was noticeably less yellow than the wild-type (suggesting a failure to bind FAD) and no activity could be detected. Supplementation of the reaction with FAD restored activity, but the Hill coefficient was similar to that of wild-type. However, altering Gly150 to serine increased h to almost one in both the presence and absence of exogenous FAD (ΔΔG approximately 1 kJmol-1) (Figure 1b and Table 1). Like the wild-type protein, all three glycine-to-serine substitutions showed no cooperativity towards NADH (Figure S4 and Table 1). The serine-substituted variants showed similar stability towards limited proteolysis (Figure S6) and only slightly increased susceptibility to thermal denaturation (as judged by differential scanning fluorimetry; Table 1).Elastic network modelling of NQO1 supports a dynamical basis for negative cooperativityIn order to explore the structural basis for these observations, with a particular focus on the modulation of cooperativity within NQO1, we described the enzyme using a coarse grained dynamical approach, namely the Gaussian network model (GNM). ADDIN EN.CITE <EndNote><Cite><Author>Haliloglu</Author><Year>1997</Year><RecNum>7262</RecNum><DisplayText><style face="superscript">[23]</style></DisplayText><record><rec-number>7262</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236008">7262</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haliloglu, T.</author><author>Bahar, I.</author><author>Erman, B.</author></authors></contributors><titles><title>Gaussian dynamics of folded proteins</title><secondary-title>Physical review letters</secondary-title><alt-title>Phys. Rev. Letts.</alt-title></titles><periodical><full-title>Physical Review Letters</full-title></periodical><pages>3090</pages><volume>79</volume><number>16</number><dates><year>1997</year></dates><urls></urls></record></Cite><Cite><Author>Bahar</Author><Year>1997</Year><RecNum>7263</RecNum><record><rec-number>7263</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236115">7263</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bahar, I.</author><author>Atilgan, A. R.</author><author>Erman, B.</author></authors></contributors><titles><title>Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential</title><secondary-title>Folding and Design</secondary-title></titles><periodical><full-title>Folding and Design</full-title></periodical><pages>173-181</pages><volume>2</volume><number>3</number><dates><year>1997</year></dates><isbn>1359-0278</isbn><urls></urls></record></Cite></EndNote>[23] Such elastic network models have been widely used in characterising the global dynamics and allostery of proteins and their complexes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWhhcjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [24] In a GNM of a protein, the residues, along with cofactor and ligand where applicable, are connected by harmonic springs. The low frequency modes of motion derived from the resulting connectivity matrix can indicate key mechanical and functional features of a protein. Here we consider GNM analysis based on the X-ray structure of NQO1 in complex with ligand 1, with corresponding PDB code 2F1O. ADDIN EN.CITE <EndNote><Cite><Author>Asher</Author><Year>2006</Year><RecNum>173</RecNum><DisplayText><style face="superscript">[22]</style></DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asher, G.</author><author>Dym, O.</author><author>Tsvetkov, P.</author><author>Adler, J.</author><author>Shaul, Y.</author></authors></contributors><auth-address>Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.</auth-address><titles><title>The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol</title><secondary-title>Biochemistry</secondary-title></titles><periodical><full-title>Biochemistry</full-title></periodical><pages>6372-6378</pages><volume>45</volume><number>20</number><keywords><keyword>Animals</keyword><keyword>Apoproteins/metabolism</keyword><keyword>Benzoquinones/chemistry/metabolism</keyword><keyword>Catalytic Domain</keyword><keyword>Crystallization</keyword><keyword>Crystallography, X-Ray</keyword><keyword>Dicumarol/chemistry/metabolism</keyword><keyword>Enzyme Inhibitors/chemistry/metabolism</keyword><keyword>Humans</keyword><keyword>Indolequinones/chemistry/metabolism</keyword><keyword>Models, Molecular</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/chemistry/metabolism</keyword><keyword>Phenylalanine/metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Rats</keyword><keyword>Triazines/chemistry/metabolism</keyword><keyword>Tyrosine/metabolism</keyword></keywords><dates><year>2006</year></dates><pub-location>United States</pub-location><isbn>0006-2960; 0006-2960</isbn><urls></urls><electronic-resource-num>10.1021/bi0600087 [doi]</electronic-resource-num><access-date>May 23</access-date></record></Cite></EndNote>[22] Each monomer of NQO1 comprises a large N-terminal domain (NTD) with flavodoxin topology, involving residues 1–223; and a smaller CTD, from residues 224–273; FAD and ligand bind at the interface between the monomers (Figure 2a). Overall, the NQO1 dimer becomes slightly more compact on binding 1-4, as demonstrated by analytical ultracentrifugation (Figure S7, Table S1). For NQO1, computation of B-factors via the Gaussian network model indicates areas of mobility; these indicate higher flexibility around residues 240 - 248 in each monomer. This region corresponds to the two short helices, ?8, of the CTD (Figure 2a,b). Other regions of high B-factor value involve amino acids at the ?1-?2 junction (31 – 35), loop L3 (58 – 68), loop L9 (230 – 235), as well as CTD helix ?5 (197 – 211). These predicted high B-factor regions correspond well to those found experimentally (Figure 2a,b). 548640000Figure 1. Human NQO1 showed negative cooperativity towards dicoumarol and related compounds. (a) Hill plots for NQO1 enzymatic activity in the presence of compounds 1-4. In this type of plot, log10(v/v0-v) is plotted against log10[Inhibitor], where v0 is the maximal or uninhibited rate. In such plots, the gradient of the line equals –h, such that positive cooperativity is indicated when h > 1.0 and negative cooperativity when h < 1.0. When h = 1.0, there is no cooperativity.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbmdlbDwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [25] This method has been widely used to detect cooperative behaviour of enzymes towards their inhibitors (for example, to detect positive cooperativity in the inhibition of fructose 1,6-bisphosphatase by AMP ADDIN EN.CITE <EndNote><Cite><Author>Takata</Author><Year>1965</Year><RecNum>5051</RecNum><DisplayText><style face="superscript">[26]</style></DisplayText><record><rec-number>5051</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">5051</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Takata, K.</author><author>Pogell, B. M.</author></authors></contributors><titles><title>Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate</title><secondary-title>The Journal of biological chemistry</secondary-title></titles><periodical><full-title>The Journal of biological chemistry</full-title></periodical><pages>651-662</pages><volume>240</volume><keywords><keyword>Adenine Nucleotides</keyword><keyword>Enzyme Inhibitors</keyword><keyword>Fructose-Bisphosphatase</keyword><keyword>Glucose/metabolism</keyword><keyword>Hexosephosphates</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Liver/enzymology</keyword><keyword>Papain</keyword><keyword>Rats</keyword><keyword>Research</keyword><keyword>Thermodynamics</keyword><keyword>EXPERIMENTAL LAB STUDY</keyword><keyword>GLUCOSE METABOLISM</keyword><keyword>HEXOSEDIPHOSPHATASE</keyword><keyword>LIVER ENZYMOLOGY</keyword></keywords><dates><year>1965</year></dates><pub-location>UNITED STATES</pub-location><isbn>0021-9258; 0021-9258</isbn><urls></urls><access-date>Feb</access-date></record></Cite></EndNote>[26], to detect negative cooperativity in the fosmidomycin inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase, ADDIN EN.CITE <EndNote><Cite><Author>Mercklé</Author><Year>2005</Year><RecNum>3335</RecNum><DisplayText><style face="superscript">[27]</style></DisplayText><record><rec-number>3335</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">3335</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mercklé, L.</author><author>de Andrés-Gómez, A.</author><author>Dick, B.</author><author>Cox, R. J.</author><author>Godfrey, C. R.</author></authors></contributors><auth-address>School of Chemistry, University of Bristol, Cantock's Close, Clifton, Bristol, BS8 1TS, UK.</auth-address><titles><title>A fragment-based approach to understanding inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase</title><secondary-title>Chembiochem : a European journal of chemical biology</secondary-title></titles><periodical><full-title>Chembiochem : a European journal of chemical biology</full-title></periodical><pages>1866-1874</pages><volume>6</volume><number>10</number><keywords><keyword>Aldose-Ketose Isomerases/antagonists & inhibitors/chemistry/metabolism</keyword><keyword>Anti-Bacterial Agents/chemistry/pharmacology</keyword><keyword>Binding Sites</keyword><keyword>Enzyme Inhibitors/chemistry/pharmacology</keyword><keyword>Escherichia coli/enzymology</keyword><keyword>Fosfomycin/analogs & derivatives/chemical synthesis/chemistry/pharmacology</keyword><keyword>Kinetics</keyword><keyword>Models, Molecular</keyword><keyword>Multienzyme Complexes/antagonists & inhibitors/chemistry/metabolism</keyword><keyword>Oxidoreductases/antagonists & inhibitors/chemistry/metabolism</keyword></keywords><dates><year>2005</year></dates><pub-location>Germany</pub-location><isbn>1439-4227; 1439-4227</isbn><urls></urls><electronic-resource-num>10.1002/cbic.200500061 [doi]</electronic-resource-num><access-date>Oct</access-date></record></Cite></EndNote>[27] and to show the lack of cooperativity in the inhibition of alkaline phosphatase by l-tryptophan ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>1971</Year><RecNum>2952</RecNum><DisplayText><style face="superscript">[28]</style></DisplayText><record><rec-number>2952</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">2952</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, C. W.</author><author>Sie, H. G.</author><author>Fishman, W. H.</author></authors></contributors><titles><title>L-tryptophan. A non-allosteric organ-specific uncompetitive inhibitor of human placental alkaline phosphatase</title><secondary-title>The Biochemical journal</secondary-title></titles><periodical><full-title>The Biochemical journal</full-title></periodical><pages>509-516</pages><volume>124</volume><number>3</number><keywords><keyword>Alkaline Phosphatase/antagonists & inhibitors</keyword><keyword>Binding Sites</keyword><keyword>Bone and Bones/enzymology</keyword><keyword>Female</keyword><keyword>Hot Temperature</keyword><keyword>Humans</keyword><keyword>Intestines/enzymology</keyword><keyword>Kinetics</keyword><keyword>Liver/enzymology</keyword><keyword>Organ Specificity</keyword><keyword>Placenta/enzymology</keyword><keyword>Pregnancy</keyword><keyword>Protein Denaturation</keyword><keyword>Stereoisomerism</keyword><keyword>Thermodynamics</keyword><keyword>Tryptophan/pharmacology</keyword><keyword>Urea</keyword></keywords><dates><year>1971</year></dates><pub-location>ENGLAND</pub-location><isbn>0264-6021; 0264-6021</isbn><urls></urls><access-date>Sep</access-date></record></Cite></EndNote>[28]). Each point represents the mean of three separate determinations, the error bars are standard deviations of these means and the lines are linear best fits to the data. Hill coefficients are given on the graphs. (b) Hill plots were constructed for the glycine to serine variants with 300 μM NADH, 70 μM DCPIP and varying concentrations of dicoumarol. Reactions were measured at 37 °C using 5 nM G149S-NQO1, 5 nM and 8 nM G150S-NQO1; the activity of G174S-NQO1 was too low to measure in the absence of additional FAD. These plots were used to estimate the Hill coefficient (h). Each point represents the mean of three separate determinations and the error bars show the standard error of these means; triplicate Hill plots were constructed, one representative plot with a median value of h shown. This was repeated in excess FAD for each enzyme (each enzyme stock was pre-diluted using FAD containing buffer such that it was 10x the concentration of active sites in the diluted stock; enzyme concentrations were decreased to account for the higher activity in the presence of FAD: G149S-NQO1, 2.5 nM; G150S-NQO1, 5 nM; G174S-NQO1, 10 nM).Table 1: Kinetic and stability parameters for wild-type NQO1 and glycine to serine substituted variants. hdicoumarol(ΔΔG kJmol-1)hNADH(ΔΔG kJmol-1)Km,appNADH?Mkcat,apps-1kcat/KmμM-1sTm°C-FAD+FADWild type0.56 ±0.01(4.9)0.47 ±0.09(6.1)1.05 ±0.05(-0.5)240 ±34186 ±120.78±0.1649.17 ±0.47NQO1- G149S0.39 ±0.05(7.3)0.47 ±0.03(6.1)0.99 ±0.09(0.1)570 ±161135 ±210.24±0.1046.10 ±0.53NQO1- G150S0.90 ±0.19(1.0)0.94 ±0.06(0.6)1.07 ±0.08(-0.7)265 ±64126 ±140.48±0.1747.57 ±0.40NQO1- G174SActivity too low0.57 ±0.05(4.7)1.09 ±0.02(-0.9)307 ±3578 ±40.25±0.0446.43 ±0.32Kinetic measurements used wild type NQO1 (3 nM dimer), NQO1- G149S (3 nM dimer), NQO1-G150S (3 nM dimer) and NQO1-G174S (20 nM dimer) with 70 μM DCPIP at 37 °C. Non-enzymatic background rates were measured in triplicate at each concentration of NADH and 70 μM DCPIP at 37 °C in 50 mM phosphate buffer pH 7.4 and the mean of these subtracted from the rates obtained from the linear section at the beginning of each progress curve with enzyme included (also in triplicate). Melting temperatures (Tm) were determined (in triplicate) by DSF.Figure 2: (a) Experimental B-factors for atoms of crystal structure of NQO1 (largest values in red), ADDIN EN.CITE <EndNote><Cite><Author>Asher</Author><Year>2006</Year><RecNum>173</RecNum><DisplayText><style face="superscript">[22]</style></DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asher, G.</author><author>Dym, O.</author><author>Tsvetkov, P.</author><author>Adler, J.</author><author>Shaul, Y.</author></authors></contributors><auth-address>Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.</auth-address><titles><title>The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol</title><secondary-title>Biochemistry</secondary-title></titles><periodical><full-title>Biochemistry</full-title></periodical><pages>6372-6378</pages><volume>45</volume><number>20</number><keywords><keyword>Animals</keyword><keyword>Apoproteins/metabolism</keyword><keyword>Benzoquinones/chemistry/metabolism</keyword><keyword>Catalytic Domain</keyword><keyword>Crystallization</keyword><keyword>Crystallography, X-Ray</keyword><keyword>Dicumarol/chemistry/metabolism</keyword><keyword>Enzyme Inhibitors/chemistry/metabolism</keyword><keyword>Humans</keyword><keyword>Indolequinones/chemistry/metabolism</keyword><keyword>Models, Molecular</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/chemistry/metabolism</keyword><keyword>Phenylalanine/metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Rats</keyword><keyword>Triazines/chemistry/metabolism</keyword><keyword>Tyrosine/metabolism</keyword></keywords><dates><year>2006</year></dates><pub-location>United States</pub-location><isbn>0006-2960; 0006-2960</isbn><urls></urls><electronic-resource-num>10.1021/bi0600087 [doi]</electronic-resource-num><access-date>May 23</access-date></record></Cite></EndNote>[22] FAD and ligand 1 in green; (b) Comparison of computed (black) and experimental (blue) B-factor values across NQO1 residues. Magnitude of motion for modes (c) k=1; (d) k=2; and (e) k=3 (red, most mobile; blue, least mobile). Dynamic domains for (f) k=1; (g) k=2; and (h) k=3. The domains are separated by the signs of eigenvectors and colored red (+) and blue (-) respectively.Using the Gaussian network model, we consider the predicted fluctuation profiles of the most global modes of motion for apo NQO1, with ligand 1 removed from both sites. We observe that these slowest frequency modes appear to represent strongly collective motions of NQO1: for the lowest frequency mode, labelled k=1, the higher amplitude motions of the protein (red regions in Figure 2c) appear to belong to the NTD regions of the monomers. We note that blue region in Figure 2c indicates lower motion and defines a hinge region. For mode k=2, the mobility of NQO1 also involves CTD residues belonging to the ?8 helices of both monomers (Figure 2d). For the k=3 mode, only one of the two ?8 helices is engaged (Figure 2e). In terms of the direction of these motions, the k=1 and k=2 modes involve cross-monomer antisymmetric movement of NQO1 (Figure 2f,g) whereas for k=3, the monomers appear to librate separately in a wagging motion (Figure 2h). For all three modes, however, the interface for anticorrelated domain dynamics intersects with both NQO1 active sites (Figure 2f-h). We may quantify the non-local nature of these soft modes by computing their collectivity, ?k (see Methods). ADDIN EN.CITE <EndNote><Cite><Author>Brüschweiler</Author><Year>1995</Year><RecNum>7266</RecNum><DisplayText><style face="superscript">[29]</style></DisplayText><record><rec-number>7266</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236490">7266</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brüschweiler, R.</author></authors></contributors><titles><title>Collective protein dynamics and nuclear spin relaxation</title><secondary-title>The Journal of chemical physics</secondary-title></titles><periodical><full-title>The Journal of chemical physics</full-title></periodical><pages>3396-3403</pages><volume>102</volume><number>8</number><dates><year>1995</year></dates><isbn>0021-9606</isbn><urls></urls></record></Cite></EndNote>[29] In all cases, the modes are global motions, with collectivity values of 0.62, 0.52 and 0.46 for the respective k=1, k=2 and k=3 modes, ie. for the k=1 mode, 62% of the NQO1 residues are involved in these modes respectively (Figure S8). The collectivity of other modes dimishes only slowly with increased frequency, eg. ?k has a value of 0.33 for mode k=20 (Figure S8).133350-498221000Next, we considered the effect on the dynamics of NQO1 by introducing ligand 1 at one of protein’s two active sites. For the three softest modes of the NQO1 complex, the magnitude and direction of the motions remain qualitatively similar to that of the apo protein modes shown in Figure 2c-h. Nevertheless, there are differences in the detailed motion of the protein predicted on ligand association: as perhaps might be expected, there is a significant decrease in mode motion of active site residues in the vicinity of the bound ligand (Figure 3a); for example, for k=1, this is most notable for residues 115 - 150; this region includes active site residue Tyr128, the mobility of which drops by 62% on ligand binding (Figure 3a). 10470114378100Figure 3. (a) Difference in magnitudes of motion on ligand 1 binding (computed as apo – complexed), for modes k=1 (black), 2 (blue) and 3 (red); (b) Difference in mode motion on ligand 1 binding of summed ten slowest modes of motion. By contrast, in some parts of the enzyme, there is an increase in mode motion on ligand binding. For k=1, this occurs mainly at NTD helix ?5 that traverses NQO1 (residues 196 – 210, Figure 3a); the spatial location of ?5 is shown in Figure 2a. For k=2, increasing mobility on ligand association is found at helices ?1 (residues 11 - 44) and again at ?5 (Figures 2a and 3a). Finally, for the k=3 mode, residues 51 – 91 and 150 – 164 are more mobile on complexation (Figure 3a), The first region includes loop L3 (Figure 2a) which is highlighted as a flexible region from B-factors (Figure 2b) and from previous work.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWRpbmEtQ2FybW9uYSA8L0F1dGhvcj48WWVhcj4yMDE2
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ADDIN EN.CITE.DATA [6a, 6c] Interestingly, residues 15 – 164 correspond to loop L6 in the second, unoccupied binding site (Figure 2a). These amino acids are remote to the binding site, although we note there is an equal and opposite effect from mode 2. Overall, considering the cumulative contribution of the 10 slowest modes (Figure 3b), on binding of 1, the motion is damped around the ligand binding site and a neighbouring shell of residues centred around Gly180 and Phe181. By contrast, there is an increase in flexibility around amino acids 242 – 251, i.e. helix ?8 in the CTD.3274695000To further probe the sensitivity of amino acids in NQO1 to receiving and propagating mechanical signals, we applied perturbation-response scanning (PRS) to the Gaussian network model of the protein.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdGlsZ2FuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA [30] From PRS analysis, a range of residues across NQO1 appear to be sensitive to perturbation (black, Figure 4), with peaks in signal profile at secondary structure elements ?1, ?7, ?4-L6 and ?5 in the NTD and ?8 in the CTD. This pattern is broadly reflected by the profile of residues which are effective in propagating signal through the protein (red, Figure 4). Clearly, NQO1 forms a highly collective dynamic network of amino acids, capable of responding to ligand binding and communicating that response through the protein. left87966500Specifically, PRS suggests that the ?8 helix, residues 242-251 of the CTD, would respond (Figure 4) to the increase in mode motion on ligand binding (Figure 3b) and would be capable of propagating this signal remotely throughout the protein, including to regions such as loop L6 near the second binding site, potentially impairing binding of a second ligand at that site. Figure 4. Magnitude of perturbation (black) and response (red) signal of receiver and propagator residues respectively in apo NQO1 model. Given this highly interconnected network of residues in NQO1, sensitive to ligand binding, it is perhaps surprising that only the G150S variant led to abrogation of negative cooperativity, whereas G149S and G174S variants did not (Table 1). The slow modes of NQO1 computed from the Gaussian network model indicate that residues Gly149 and Gly150, and to a lesser extent, Gly174, lie in regions of near-zero mode motion (Figure 3b); residues with low motion have been shown in elastic network studies of other proteins to point towards significant hinge or functional residues within a macromolecule. ADDIN EN.CITE <EndNote><Cite><Author>Yang</Author><Year>2005</Year><RecNum>7269</RecNum><DisplayText><style face="superscript">[31]</style></DisplayText><record><rec-number>7269</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236840">7269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yang, L. W.</author><author>Bahar, I.</author></authors></contributors><auth-address>Department of Computational Biology, school of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.</auth-address><titles><title>Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes</title><secondary-title>Structure</secondary-title><alt-title>Structure (London, England : 1993)</alt-title></titles><alt-periodical><full-title>Structure (London, England : 1993)</full-title></alt-periodical><pages>893-904</pages><volume>13</volume><number>6</number><edition>2005/06/09</edition><keywords><keyword>Binding Sites</keyword><keyword>Catalysis</keyword><keyword>Computational Biology</keyword><keyword>Computer Simulation</keyword><keyword>Enzyme Stability</keyword><keyword>Enzymes/*chemistry/*metabolism</keyword><keyword>Ligands</keyword><keyword>Models, Molecular</keyword><keyword>Motion</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Substrate Specificity</keyword><keyword>Thermodynamics</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0969-2126 (Print)
0969-2126</isbn><accession-num>15939021</accession-num><urls></urls><custom2>PMC1489920</custom2><custom6>NIHMS9262</custom6><electronic-resource-num>10.1016/j.str.2005.03.015</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31] Indeed, all three glycines lie near the ligand binding site (Figure 5a) and the backbones of Gly149 and Gly150 play a specific role in hydrogen bonding with the isoalloxazine ring of FAD. However, from inspection of the NQO1/1 crystal structure, we note that perturbation to serine of Gly150, but not Gly149 or Gly174, would directly obstruct the substrate/inhibitor binding site (Figure 5b). This in turn could lead to displacement of immediately neighboring residues (Tyr126, Tyr128), second shell residues (Gly180, Phe181) and beyond this, the CTD helix ?8 residues 242 - 251 (Figure 5b), interfering with the negatively cooperative communication between active sites.Figure 5. (a) Location of Gly149, Gly150 and Gly174 at active site of NQO1 (monomers coloured red and blue; FAD and 1 in green). (b) Spatial relationship of Gly149 and Gly150 to promixal residues linked to inter-active site communication. ConclusionsThese findings have considerable implications for the function of the protein in vivo and its exploitation as an anti-cancer drug target. Our studies imply that, in addition to adopting a correctly folded three-dimensional structure, NQO1 displays highly collective inter-domain and inter-monomer dynamics. This coupled network of amino acids is sensitive to ligand binding and can be disrupted by a single amino acid change, with functional consequences for the protein. Therefore, it is possible that the cancer-associated polymorphisms exert their pathogenic effect, in part, through alteration of the dynamics of the protein. This hypothesis is supported by recent studies demonstrating that the P187S variant of NQO1 is more likely to populate partially unfolded states.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWRpbmEtQ2FybW9uYTwvQXV0aG9yPjxZZWFyPjIwMTc8
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ADDIN EN.CITE.DATA [32] In addition, the ability of NQO1 to prevent degradation of proteins via the 20S proteosome is NADH-dependent which also suggests an underlying redox sensing mechanism for the chaperone function of NQO1. ADDIN EN.CITE <EndNote><Cite><Author>Asher</Author><Year>2001</Year><RecNum>174</RecNum><DisplayText><style face="superscript">[10a]</style></DisplayText><record><rec-number>174</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">174</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asher, G.</author><author>Lotem, J.</author><author>Cohen, B.</author><author>Sachs, L.</author><author>Shaul, Y.</author></authors></contributors><auth-address>Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.</auth-address><titles><title>Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title></periodical><pages>1188-1193</pages><volume>98</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Apoptosis/drug effects/physiology/radiation effects</keyword><keyword>COS Cells</keyword><keyword>Cell Survival/drug effects/physiology</keyword><keyword>Cercopithecus aethiops</keyword><keyword>Colonic Neoplasms</keyword><keyword>Dicumarol/pharmacology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Inbred BALB C</keyword><keyword>Quinone Reductases/genetics/metabolism</keyword><keyword>Recombinant Proteins/metabolism</keyword><keyword>T-Lymphocytes/cytology/physiology</keyword><keyword>Transfection</keyword><keyword>Tumor Cells, Cultured</keyword><keyword>Tumor Suppressor Protein p53/metabolism</keyword></keywords><dates><year>2001</year></dates><pub-location>United States</pub-location><isbn>0027-8424; 0027-8424</isbn><urls></urls><electronic-resource-num>10.1073/pnas.021558898</electronic-resource-num><access-date>Jan 30</access-date></record></Cite></EndNote>[10a] Coumarin-based inhibitors such as dicoumarol (1) compete with NADH for binding to NQO1 and thereby target p53 for degradation. Although the precise mechanism for this is unclear, it is likely to involve direct interactions between NQO1 and p53. ADDIN EN.CITE <EndNote><Cite><Author>Anwar</Author><Year>2003</Year><RecNum>135</RecNum><DisplayText><style face="superscript">[33]</style></DisplayText><record><rec-number>135</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">135</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anwar, A.</author><author>Dehn, D.</author><author>Siegel, D.</author><author>Kepa, J. K.</author><author>Tang, L. J.</author><author>Pietenpol, J. A.</author><author>Ross, D.</author></authors></contributors><auth-address>Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver 80262, USA.</auth-address><titles><title>Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems</title><secondary-title>The Journal of biological chemistry</secondary-title></titles><periodical><full-title>The Journal of biological chemistry</full-title></periodical><pages>10368-10373</pages><volume>278</volume><number>12</number><keywords><keyword>Cell-Free System</keyword><keyword>Humans</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/analysis/chemistry</keyword><keyword>Nuclear Proteins</keyword><keyword>Precipitin Tests</keyword><keyword>Proto-Oncogene Proteins/chemistry</keyword><keyword>Proto-Oncogene Proteins c-mdm2</keyword><keyword>Tumor Cells, Cultured</keyword><keyword>Tumor Suppressor Protein p53/analysis/chemistry</keyword></keywords><dates><year>2003</year></dates><pub-location>United States</pub-location><isbn>0021-9258; 0021-9258</isbn><urls></urls><electronic-resource-num>10.1074/jbc.M211981200</electronic-resource-num><access-date>Mar 21</access-date></record></Cite></EndNote>[33] Negative cooperativity occurs only with inhibitors and not with NAD(P)H. One consequence of negative cooperativity is to dampen the responsiveness of a system. Some enzymes involved in signalling exhibit negative cooperativity and, consequently, are switched on over a wide range of substrate concentrations. ADDIN EN.CITE <EndNote><Cite><Author>Ferrell</Author><Year>2009</Year><RecNum>1386</RecNum><DisplayText><style face="superscript">[34]</style></DisplayText><record><rec-number>1386</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713203">1386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferrell, J. E., Jr.</author></authors></contributors><auth-address>Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA. james.ferrell@stanford.edu</auth-address><titles><title>Q&A: Cooperativity</title><secondary-title>Journal of biology</secondary-title></titles><periodical><full-title>Journal of biology</full-title></periodical><pages>53</pages><volume>8</volume><number>6</number><keywords><keyword>Algorithms</keyword><keyword>Allosteric Regulation</keyword><keyword>Allosteric Site</keyword><keyword>Animals</keyword><keyword>Hemoglobins/chemistry/metabolism</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Oxygen/chemistry/metabolism</keyword><keyword>Protein Binding</keyword></keywords><dates><year>2009</year></dates><pub-location>England</pub-location><isbn>1475-4924; 1475-4924</isbn><urls></urls><electronic-resource-num>10.1186/jbiol157; 10.1186/jbiol157</electronic-resource-num></record></Cite></EndNote>[34] It is possible that a similar situation occurs here: NQO1’s negatively cooperative response to inhibitors may result in inhibition of the p53 interaction over a wide range of concentrations. 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ADDIN EN.CITE.DATA [14a]Cell lines and cell culture: Cells were maintained at 37 °C in exponential phase in a humidified incubator with 5% CO2. HCT116 colon carcinoma cells were grown in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% (v/v) heat-inactivated foetal calf serum and 2 mM L-glutamine. MCF10A breast epithelial cells were maintained in DMEM/F-12 (1:1) containing L-glutamine (2 mM), horse serum (5%), epidermal growth factor (20 ?g/mL), hydrocortisone (0.5 ?g/mL), cholera toxin (0.1 ?g/mL), insulin (10 ?g/mL) and penicillin/streptomycin (1%). Human umbilical vein endothelial cells (HUVECs) were obtained from TCS CellWorks (Buckingham, UK) and cultured as per the supplier’s instructions. Cells were used between passages 2-16 (HCT116 and MCF10A) and 2-8 (HUVECs).Western blot analysis of p53 levels: Exponentially growing cells were seeded at 105 cells/well in six well plates, left to adhere overnight, then treated with or without 10 ?M etoposide for 24 h prior to treatment with 50, 100, 200 or 400 ?M of each inhibitor and incubated for four hours. Cells were harvested by scraping into lysis buffer (50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM EDTA, 0.5% v/v Nonidet P-40, 1 mM dithiothreitol, 1 mM phenylmethanesulphonyl fluoride, 2 mM sodium orthovanadate, 2 mM sodium fluoride, 20 mM β-glycerolphosphate, 5 mM sodium pyrophosphate, and 1 mg/ml Protease Inhibitor Cocktail tablet (Roche, UK). Samples were then sonicated on ice and the protein concentration of each was estimated using the BCA assay. For each sample, 40 ?g protein was loaded and electrophoresed. p53 antibody (DO-1, Insight Biotechnology, Middlesex, UK) was used to assess p53 protein levels, while β-actin or tubulin antibodies were used as loading controls. Primary antibodies were then detected using the appropriate HRP-conjugated secondary antibody and bands were visualized using the ECL detection system (GE Healthcare, Buckinghamshire, UK). Exponentially growing HUVECs were seeded at (2.5 x105 cells/well) in six well plates and left to adhere overnight, before exposure to 10 Gy ionizing radiation (250 kV X-rays). The cells were then incubated for 4 h with and without the inhibitor before being harvested and probed for p53 as described above.Measurement of NQO1 kinetics and inhibition: Recombinant human NQO1 was either a gift from Professor David Ross and Dr David Siegel or prepared as described previously ADDIN EN.CITE <EndNote><Cite><Author>Pey</Author><Year>2014</Year><RecNum>4011</RecNum><DisplayText><style face="superscript">[16a]</style></DisplayText><record><rec-number>4011</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4011</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pey, A. L.</author><author>Megarity, C. F.</author><author>Timson, D. J.</author></authors></contributors><auth-address>Department of Physical Chemistry, Faculty of Sciences, University of Granada, Av. Fuentenueva s/n, 18071, Spain. Electronic address: angelpey@ugr.es.; School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn (TRUNCATED)</auth-address><titles><title>FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1</title><secondary-title>Biochimica et biophysica acta</secondary-title></titles><periodical><full-title>Biochimica et biophysica acta</full-title></periodical><pages>2163-2173</pages><volume>1842</volume><number>11</number><keywords><keyword>Cancer-associated polymorphism</keyword><keyword>Kinetic instability</keyword><keyword>NAD(P)H quinone oxidoreductase 1</keyword><keyword>NQO12</keyword><keyword>NQO13</keyword></keywords><dates><year>2014</year></dates><publisher>Elsevier B.V</publisher><isbn>0006-3002; 0006-3002</isbn><urls></urls><electronic-resource-num>S0925-4439(14)00264-6 [pii]</electronic-resource-num><access-date>Aug 29</access-date></record></Cite></EndNote>[16a]. Reduction of dichlorophenolindophenol (DCPIP) by NADH was measured spectrophotometrically at 600 nm at 37 °C in 50 mM sodium phosphate buffer (pH 7.4). For measurement of wild-type NQO1 with NAD(P)H and inhibition of wild-type NQO1 by 1-4 in the presence of 200 μM NADH a Cary 100 Scan UV-visible spectrophotometer was used with 40 μM DCPIP and 40 μM NQO1 in a total reaction volume of 900 μl. For inhibition of glycine to serine variant forms of NQO1 by 1 a Multiskan Spectrum platereader (Thermo Scientific) was used with 300 ?M NADH, 70 ?M DCPIP, 3-20 nM NQO1 and 0.9 μM lysozyme in a total volume of 200 μl . ADDIN EN.CITE <EndNote><Cite><Author>Pey</Author><Year>2014</Year><RecNum>4011</RecNum><DisplayText><style face="superscript">[16a]</style></DisplayText><record><rec-number>4011</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4011</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pey, A. L.</author><author>Megarity, C. F.</author><author>Timson, D. J.</author></authors></contributors><auth-address>Department of Physical Chemistry, Faculty of Sciences, University of Granada, Av. Fuentenueva s/n, 18071, Spain. Electronic address: angelpey@ugr.es.; School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn (TRUNCATED)</auth-address><titles><title>FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1</title><secondary-title>Biochimica et biophysica acta</secondary-title></titles><periodical><full-title>Biochimica et biophysica acta</full-title></periodical><pages>2163-2173</pages><volume>1842</volume><number>11</number><keywords><keyword>Cancer-associated polymorphism</keyword><keyword>Kinetic instability</keyword><keyword>NAD(P)H quinone oxidoreductase 1</keyword><keyword>NQO12</keyword><keyword>NQO13</keyword></keywords><dates><year>2014</year></dates><publisher>Elsevier B.V</publisher><isbn>0006-3002; 0006-3002</isbn><urls></urls><electronic-resource-num>S0925-4439(14)00264-6 [pii]</electronic-resource-num><access-date>Aug 29</access-date></record></Cite></EndNote>[16a] Reactions were initiated by the addition of NQO1 and rates were measured for 2 min at 37 °C. 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ADDIN EN.CITE.DATA [36] This method enable the estimation of difference in free energy of binding between the high and low affinity states of the protein (ΔΔG). It makes a number of assumptions. First that cooperativity can be represented by two equilibria: K1, the dissociation constant for the ligand and the unliganded enzyme and K2, the dissociation constant for the ligand and enzyme already bound to one ligand molecule (i.e. these are “macroscopic” binding constants which reflect the overall ligand occupancy of the protein). In the case of negative cooperativity, K2 will be greater than (i.e. lower affinity) than K1. Second, that in the unliganded enzyme, the affinities of the two binding sites for the inhibitor are equal (i.e. that the “microscopic” binding constants for the two active sites are the same). This would be expected in a homodimeric enzyme like NQO1. However, it should be noted that there is no positive evidence in favour of this assumption. Thus, the ΔΔG values reported here should be seen as minimum values.The Hill coefficient is related to these two equilibrium constants by the equation:h=4K2K11+2K2K1The difference in free energies can be calculated according to the equation:??G=-RTloge4K2K1Where, R is the universal gas constant and T is the absolute (Kelvin) temperature.Ultracentrifugation: NQO1 was buffer exchanged and further purified on a Superdex 200 10/30 gel filtration column (GE-Lifesciences) in PBS. Peak fractions were pooled and diluted in buffer with or without the addition of inhibitors to a final concentration 15 ?M. Samples were then loaded into a two-sector Epon filled centerpiece covered with quartz glass windows and centrifuged at 45000 rpm at 20 °C. Sedimentation was monitored every 90 s using absorbance at 450 nm until full sedimentation had been reached. The data were analysed using Sedfit software. ADDIN EN.CITE <EndNote><Cite><Author>Schuck</Author><Year>2000</Year><RecNum>4573</RecNum><DisplayText><style face="superscript">[37]</style></DisplayText><record><rec-number>4573</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4573</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schuck, P.</author></authors></contributors><auth-address>Molecular Interactions Resource, Bioengineering and Physical Science Program, ORS, National Institutes of Health, Bethesda, Maryland 20892, USA. pschuck@helix.</auth-address><titles><title>Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling</title><secondary-title>Biophysical journal</secondary-title></titles><periodical><full-title>Biophysical journal</full-title></periodical><pages>1606-1619</pages><volume>78</volume><number>3</number><keywords><keyword>Confidence Intervals</keyword><keyword>Diffusion</keyword><keyword>Models, Theoretical</keyword><keyword>Molecular Weight</keyword><keyword>Proteins/chemistry/isolation & purification</keyword><keyword>Software</keyword><keyword>Ultracentrifugation/methods</keyword></keywords><dates><year>2000</year></dates><pub-location>UNITED STATES</pub-location><isbn>0006-3495; 0006-3495</isbn><urls></urls><electronic-resource-num>S0006-3495(00)76713-0 [pii]</electronic-resource-num><access-date>Mar</access-date></record></Cite></EndNote>[37]Isothermal titration calorimetry of ligand binding: Ligand binding to NQO1 was studied at 25 °C using a VP-ITC microcalorimeter (Microcal Inc, MA). Data acquisition and analysis were carried out using ORIGIN 7.0 (Microcal Inc., MA). Ligand binding was quantified by fitting the evolved heat per injection to the standard Wiseman equation. Fitting of the binding isotherm was carried out through multiple iterations until a minimum 2 value was obtained. Reported values are the average of at least three runs. NQO1 monomer concentration was chosen so as to give c values in the 100-300 range (typically 3-5 ?M). Both NQO1 and ligands were dissolved in 50 mM phosphate pH 7.5 buffer containing 5 mM FAD and 2.5% (v/v) DMSO.NQO1 protein stability: Differential scanning fluorimetry was performed as described previously, taking advantage of the increase in the natural fluorescence of the FAD molecules which occurs when the cofactor is released as the protein denatures.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWdhcml0eTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA [18, 38] Limited proteolysis with increasing concentrations of chymotrypsin (0, 5, 10, 35, 60, 90, 360, 630 nM) was performed with wild-type and variant NQO1 protein (10 μM dimer) which had been pre-incubated at 37 °C for 15 min. The reaction was allowed to proceed for 30 min after which time it was stopped by addition of an equal volume of tris-tricine SDS loading buffer (12 % (w/v) SDS; 6 % (w/v) DTT; 30 % (v/v) glycerol; 150 mM Tris/HCl pH 7). Reactions were analysed using tris-tricine SDS PAGE. ADDIN EN.CITE <EndNote><Cite><Author>Schagger</Author><Year>2006</Year><RecNum>4529</RecNum><DisplayText><style face="superscript">[39]</style></DisplayText><record><rec-number>4529</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713204">4529</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schagger, H.</author></authors></contributors><auth-address>Molekulare Bioenergetik, Zentrum der Biologischen Chemie, Universitatsklinikum Frankfurt, Theodor-Stern-Kai 7, Haus 26, D-60590 Frankfurt, Germany. schagger@zbc.kgu.de</auth-address><titles><title>Tricine-SDS-PAGE</title><secondary-title>Nature protocols</secondary-title></titles><periodical><full-title>Nature protocols</full-title></periodical><pages>16-22</pages><volume>1</volume><number>1</number><keywords><keyword>Acrylamide/chemistry</keyword><keyword>Electrophoresis, Polyacrylamide Gel/methods</keyword><keyword>Glycine/analogs & derivatives/chemistry</keyword><keyword>Hydrophobic and Hydrophilic Interactions</keyword><keyword>Molecular Probe Techniques</keyword><keyword>Proteins/analysis/chemistry/isolation & purification</keyword><keyword>Proteomics/methods</keyword><keyword>Rosaniline Dyes</keyword><keyword>Silver Staining</keyword></keywords><dates><year>2006</year></dates><pub-location>England</pub-location><isbn>1750-2799; 1750-2799</isbn><urls></urls><electronic-resource-num>10.1038/nprot.2006.4</electronic-resource-num></record></Cite></EndNote>[39]Elastic network modelling: For generating the GNM models, the coordinates of the crystal structure of NQO1 bound to ligands 1 were taken from PDB code 2F1O ADDIN EN.CITE <EndNote><Cite><Author>Asher</Author><Year>2006</Year><RecNum>173</RecNum><DisplayText><style face="superscript">[22]</style></DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1443713202">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asher, G.</author><author>Dym, O.</author><author>Tsvetkov, P.</author><author>Adler, J.</author><author>Shaul, Y.</author></authors></contributors><auth-address>Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.</auth-address><titles><title>The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol</title><secondary-title>Biochemistry</secondary-title></titles><periodical><full-title>Biochemistry</full-title></periodical><pages>6372-6378</pages><volume>45</volume><number>20</number><keywords><keyword>Animals</keyword><keyword>Apoproteins/metabolism</keyword><keyword>Benzoquinones/chemistry/metabolism</keyword><keyword>Catalytic Domain</keyword><keyword>Crystallization</keyword><keyword>Crystallography, X-Ray</keyword><keyword>Dicumarol/chemistry/metabolism</keyword><keyword>Enzyme Inhibitors/chemistry/metabolism</keyword><keyword>Humans</keyword><keyword>Indolequinones/chemistry/metabolism</keyword><keyword>Models, Molecular</keyword><keyword>NAD(P)H Dehydrogenase (Quinone)/chemistry/metabolism</keyword><keyword>Phenylalanine/metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Rats</keyword><keyword>Triazines/chemistry/metabolism</keyword><keyword>Tyrosine/metabolism</keyword></keywords><dates><year>2006</year></dates><pub-location>United States</pub-location><isbn>0006-2960; 0006-2960</isbn><urls></urls><electronic-resource-num>10.1021/bi0600087 [doi]</electronic-resource-num><access-date>May 23</access-date></record></Cite></EndNote>[22] using chains B and D. FAD was modelled by springs centred on atoms C7, N5, N3, C1’, C4’, P, PA, C4b and N9a. The ligand was modelled by atoms C5, C1 and C15. The C? atoms of the amino acids, and these ligand atoms where relevant, were used to build the Kirchhoff connectivity matrices ? using a cutoff rc of 7.3 ?. For N residues in a molecular system, diagonalization of ? provides N-1 modes; the resulting modes k of eigenvector uk with the smallest eigenvalue ?k correspond to softest and most cooperative motions within the molecular system. Contribution to motion of mode k is computed as ?Ri??Rjk=3kBT/γλk-1ukukTij where ?Ri is the Gaussian fluctuation in position of residue i, kB is Boltzmann’s constant, T is temperature and ? is the network force constant. Differences in mode motion are computed as the square displacement of residues driven by a given mode of complexed NQO1 subtracted from that of apo NQO1. Following Brüschweiler, ADDIN EN.CITE <EndNote><Cite><Author>Brüschweiler</Author><Year>1995</Year><RecNum>7266</RecNum><DisplayText><style face="superscript">[29]</style></DisplayText><record><rec-number>7266</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236490">7266</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brüschweiler, R.</author></authors></contributors><titles><title>Collective protein dynamics and nuclear spin relaxation</title><secondary-title>The Journal of chemical physics</secondary-title></titles><periodical><full-title>The Journal of chemical physics</full-title></periodical><pages>3396-3403</pages><volume>102</volume><number>8</number><dates><year>1995</year></dates><isbn>0021-9606</isbn><urls></urls></record></Cite></EndNote>[29] the level of collectivity, Ωk, for a mode k is defined as Ωk=1/Nexp-iuk,i2lnuk,i2 for N residues i. GNM analysis was performed using the iGNM 2.0 conformational dynamics interface and database. ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2016</Year><RecNum>7268</RecNum><DisplayText><style face="superscript">[30b]</style></DisplayText><record><rec-number>7268</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236719">7268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, H.</author><author>Chang, Y. Y.</author><author>Yang, L. W.</author><author>Bahar, I.</author></authors></contributors><auth-address>Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15213, USA.
Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 300, Taiwan.
Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 300, Taiwan bahar@pitt.edu.
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15213, USA lwyang@life.nthu.edu.tw.</auth-address><titles><title>iGNM 2.0: the Gaussian network model database for biomolecular structural dynamics</title><secondary-title>Nucleic Acids Res</secondary-title><alt-title>Nucleic acids research</alt-title></titles><alt-periodical><full-title>Nucleic acids research</full-title></alt-periodical><pages>D415-D422</pages><volume>44</volume><number>D1</number><edition>2015/11/20</edition><keywords><keyword>DNA/chemistry</keyword><keyword>*Databases, Protein</keyword><keyword>*Models, Molecular</keyword><keyword>Normal Distribution</keyword><keyword>*Protein Conformation</keyword><keyword>Protein Structure, Tertiary</keyword><keyword>RNA/chemistry</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan 4</date></pub-dates></dates><isbn>0305-1048</isbn><accession-num>26582920</accession-num><urls></urls><custom2>PMC4702874</custom2><electronic-resource-num>10.1093/nar/gkv1236</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[30b] Perturbation response scanning ADDIN EN.CITE <EndNote><Cite><Author>Yang</Author><Year>2005</Year><RecNum>7269</RecNum><DisplayText><style face="superscript">[31]</style></DisplayText><record><rec-number>7269</rec-number><foreign-keys><key app="EN" db-id="zefzt9rxi2dad9eztr1pzts8z0sf5esvreps" timestamp="1557236840">7269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yang, L. W.</author><author>Bahar, I.</author></authors></contributors><auth-address>Department of Computational Biology, school of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.</auth-address><titles><title>Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes</title><secondary-title>Structure</secondary-title><alt-title>Structure (London, England : 1993)</alt-title></titles><alt-periodical><full-title>Structure (London, England : 1993)</full-title></alt-periodical><pages>893-904</pages><volume>13</volume><number>6</number><edition>2005/06/09</edition><keywords><keyword>Binding Sites</keyword><keyword>Catalysis</keyword><keyword>Computational Biology</keyword><keyword>Computer Simulation</keyword><keyword>Enzyme Stability</keyword><keyword>Enzymes/*chemistry/*metabolism</keyword><keyword>Ligands</keyword><keyword>Models, Molecular</keyword><keyword>Motion</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Substrate Specificity</keyword><keyword>Thermodynamics</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0969-2126 (Print)
0969-2126</isbn><accession-num>15939021</accession-num><urls></urls><custom2>PMC1489920</custom2><custom6>NIHMS9262</custom6><electronic-resource-num>10.1016/j.str.2005.03.015</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31] is a method to compute the influence/sensitivity that each residue has on/to every other residue. Based on linear response theory, PRS is achieved by exerting a force of a given magnitude on the network, one residue at a time, and observe the response of the overall network. PRS30 was used to identify the most sensitive residues of NQO1.AcknowledgementsWe are indebted to Professor David Ross and Dr David Siegel (University of Colorado, USA) for a supply of recombinant human NQO1. We would also like to thank Dr Sharon Sneddon and Miss Catherine Treslove (University of Manchester, UK) for carrying out the p53 analyses in the normal cells and Prof Aaron Maule (Queen’s University, Belfast, UK) for access to equipment. RAB thanks Mark Dunstan for helpful discussions. This work was supported by grants from the Medical Research Council, G0500366 (to IJS) and the Association for International Cancer Research, 08-0152 (to IJS, KAN, RAB and RCW). CFM thanks the Department of Employment and Learning, Northern Ireland (DELNI) for a PhD studentship.Keywords: Quinone oxidoreductase ? Protein flexibility ? Elastic network model ? Enzyme cooperativity ? Cancer-associated protein ADDIN EN.REFLIST [1]a) R. Li, M. A. Bianchet, P. Talalay, L. M. Amzel, Proc Natl Acad Sci USA 1995, 92, 8846-8850; b) S. K. Beaver, N. Mesa-Torres, A. L. Pey, D. J. Timson, Biochim Biophys Acta 2019, 1867, 663-676.[2]C. Lind, P. Hochstein, L. Ernster, Arch Biochem Biophys 1982, 216, 178-185.[3]C. 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Schuck, Biophys J 2000, 78, 1606-1619.[38]F. Forneris, R. Orru, D. Bonivento, L. R. Chiarelli, A. Mattevi, FEBS J 2009, 276, 2833-2840.[39]H. Schagger, Nat Protoc 2006, 1, 16-22.Entry for the Table of ContentsFULL PAPER34684814331700Clare F. Megarity,-298457442200[a]Dr Clare F. Megarity, Dr Mary Clare Caraher, Dr David J. Timson, School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK[b]Dr Hoda Abdel-Aal Bettley, Dr M. Clare Caraher, Dr Katherine Scott, Dr Richard A. Bryce, Dr Karen A. Nolan, Prof Ian J. Stratford, Manchester Pharmacy School, [c] Dr Roger A. Whitehead, School of Chemistry, and [d] DrThomas A. Jowitt, The Faculty of Life Science, Manchester Cancer Research Centre and the University of Manchester, Oxford Road, Manchester, M13 9PT, UK[e]Dr Aldo Gutierrez, Department of Biosciences, Nottingham Trent University, Nottingham NG1 4BU, UK[f]Prof David J Timson, School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK; +44(0)1273 641623; d.timson@brighton.ac.ukSupporting information for this article is given via a link at the end of the document.00[a]Dr Clare F. Megarity, Dr Mary Clare Caraher, Dr David J. Timson, School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK[b]Dr Hoda Abdel-Aal Bettley, Dr M. Clare Caraher, Dr Katherine Scott, Dr Richard A. Bryce, Dr Karen A. Nolan, Prof Ian J. Stratford, Manchester Pharmacy School, [c] Dr Roger A. Whitehead, School of Chemistry, and [d] DrThomas A. Jowitt, The Faculty of Life Science, Manchester Cancer Research Centre and the University of Manchester, Oxford Road, Manchester, M13 9PT, UK[e]Dr Aldo Gutierrez, Department of Biosciences, Nottingham Trent University, Nottingham NG1 4BU, UK[f]Prof David J Timson, School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK; +44(0)1273 641623; d.timson@brighton.ac.ukSupporting information for this article is given via a link at the end of the document. Hoda Abdel-Aal Bettley, M. Clare Caraher, Katherine A. Scott, Roger C. Whitehead, Thomas A. Jowitt, Aldo Gutierrez, Richard A. Bryce, Karen A. Nolan, Ian J. Stratford, David J. Timson*Page No. – Page No.Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1)Table of contents text:NQO1 is a flavoprotein which catalyses the reduction of quinones and related compounds. The enzyme demonstrates negative cooperativity towards a competitive inhibitor, dicoumarol. A Gaussian network model, suggests that this arises from a high degree of collective motion within the protein. These findings have implications for understanding NQO1’s cellular roles and in the discovery of anticancer drugs which target the enzyme. ................
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