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Negative Cooperativity in NAD(P)H Quinone Oxidoreductase 1 (NQO1) |
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| Authors: | Dr Clare F Megarity Dr Hoda Abdel-Aal Bettley Dr M Clare Caraher Dr Katherine A Scott Dr Roger C Whitehead Dr Thomas A Jowitt Dr Aldo Gutierrez Dr Richard A Bryce Dr Karen A Nolan Prof Ian J Stratford Prof David J Timson |
| Affiliation: | 1. School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL UK;2. Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PL UK;3. School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL UK
Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PL UK;4. Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL UK;5. The Faculty of Life Science, Manchester Cancer Research Centre and the University of Manchester, Oxford Road, Manchester, M13 9PT UK;6. School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, NG11 8NS UK |
| Abstract: | NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone 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 that 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 cofactor, 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 might contribute to the biological effects of putative inhibitors of NQO1. |
| Keywords: | cancer-associated proteins elastic network models enzyme cooperativity protein flexibility quinone oxidoreductases |