title: Chloroquine binding reveals flavin redox switch function of quinone reductase 2.
abstract: Quinone reductase 2 (NQO2) is an FAD-linked enzyme and the only known human target of two antimalarial drugs, primaquine (PQ) and chloroquine (CQ). The structural differences between oxidized and reduced NQO2 and the structural basis for inhibition by PQ and CQ were investigated by x-ray crystallography. Structures of oxidized NQO2 in complex with PQ and CQ were solved at 1.4 Å resolution. CQ binds preferentially to reduced NQO2, and upon reduction of NQO2-CQ crystals, the space group changed from P2(1)2(1)2(1) to P2(1), with 1-Å decreases in all three unit cell dimensions. The change in crystal packing originated in the negative charge and 4-5º bend in the reduced isoalloxazine ring of FAD, which resulted in a new mode of CQ binding and closure of a flexible loop (Phe(126)-Leu(136)) over the active site. This first structure of a reduced quinone reductase shows that reduction of the FAD cofactor and binding of a specific inhibitor lead to global changes in NQO2 structure and is consistent with a functional role for NQO2 as a flavin redox switch.
authors.affiliation: Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Kevin K K
authors.initials: KK
authors.lastname: Leung
authors.forename: Brian H
authors.initials: BH
authors.lastname: Shilton
mesh_terms: D001665:Binding Sites; D002738:Chloroquine / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011808:Quinone Reductases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D005182:Flavin-Adenine Dinucleotide; D002738:Chloroquine; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases