3O73

Crystal structure of quinone reductase 2 in complex with the indolequinone MAC627

Summary for 3O73

• Entry DOI: 10.2210/pdb3o73/pdb
• Related: 1QR2
• Descriptor: Ribosyldihydronicotinamide dehydrogenase [quinone], ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: quinone reductase 2, nqo2, oxidoreductase, flavoprotein, indolequinone mac627, fad, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P16083
• Total number of polymer chains: 2
• Total formula weight: 56145.62

Authors

Dufour, M.,Yan, C.,Colucci, M.A.,Siegel, D.,Li, Y.,De Matteis, C.I.,Ross, D.,Moody, C.J. (deposition date: 2010-07-30, release date: 2011-05-11, Last modification date: 2023-09-06)

Primary citation

Dufour, M.,Yan, C.,Siegel, D.,Colucci, M.A.,Jenner, M.,Oldham, N.J.,Gomez, J.,Reigan, P.,Li, Y.,De Matteis, C.I.,Ross, D.,Moody, C.J.
Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition.
Chembiochem, 12:1203-1208, 2011

PubMed Abstract: A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease.

PubMed: 21506232
DOI: 10.1002/cbic.201100085

Experimental method

X-RAY DIFFRACTION (2 Å)