Negative Cooperativity in NAD(P)H Quinone Oxidoreductase 1 (NQO1)

Clare F. Megarity, 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

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2841-2849
Number of pages9
JournalChemBioChem
Volume20
Issue number22
Early online date05 Jun 2019
DOIs
Publication statusPublished - 18 Nov 2019

Keywords

  • Organic Chemistry
  • Molecular Medicine
  • Biochemistry
  • Molecular Biology

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