Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1)

Clare F. Megarity, Hoda Abdel-Aal Bettley, Mary Clare Caraher, Katherine A. Scott, Roger A. Whitehead, Thomas A. Jowitt, Aldo Gutierrez, Richard A. Bryce, Karen A. Nolan, Ian J. Stratford, David J Timson

Research output: Contribution to journalArticle

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
DOIs
Publication statusPublished - 5 Jun 2019

Bibliographical note

This is the peer reviewed version of the following article: Megarity, C. ., Abdel-Aal Bettley, H. , Caraher, M. ., Scott, K. ., Whitehead, R. ., Jowitt, T. ., Gutierrez, A. , Bryce, R. ., Nolan, K. ., Stratford, I. . and Timson, D. . (2019), Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem, which has been published in final form at doi:10.1002/cbic.201900313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Keywords

  • Quinone oxidoreductase
  • Protein flexibility
  • Elastic network model
  • Enzyme cooperativity
  • Cancer-associated protein

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  • Cite this

    Megarity, C. F., Abdel-Aal Bettley, H., Caraher, M. C., Scott, K. A., Whitehead, R. A., Jowitt, T. A., Gutierrez, A., Bryce, R. A., Nolan, K. A., Stratford, I. J., & Timson, D. J. (2019). Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem, 20(22), 2841-2849. https://doi.org/10.1002/cbic.201900313