Crystal structure of quinone reductase 2 in complex with resveratrol.
Resveratrol has been shown to have chemopreventive, cardioprotective, and antiaging properties. Here, we report that resveratrol is a potent inhibitor of quinone reductase 2 (QR2) activity in vitro with a dissociation constant of 35 nM and show that it specifically binds to the deep active-site cleft of QR2 using high-resolution structural analysis. All three resveratrol hydroxyl groups form hydrogen bonds with amino acids from QR2, anchoring a flat resveratrol molecule in parallel with the isoalloxazine ring of FAD. The unique active-site pocket in QR2 could potentially bind other natural polyphenols such as flavonoids, as proven by the high affinity exhibited by quercetin toward QR2. K562 cells with QR2 expression suppressed by RNAi showed similar properties as resveratrol-treated cells in their resistance to quinone toxicity. Furthermore, the QR2 knockdown K562 cells exhibit increased antioxidant and detoxification enzyme expression and reduced proliferation rates. These observations could imply that the chemopreventive and cardioprotective properties of resveratrol are possibly the results of QR2 activity inhibition, which in turn, up-regulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress.
Buryanovskyy
Leonid
L
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.
Fu
Yue
Y
Boyd
Molly
M
Ma
Yuliang
Y
Hsieh
Tze-chen
TC
Wu
Joseph M
JM
Zhang
Zhongtao
Z
D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D011485:Protein Binding / Q000187:drug effects; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*; D034622:RNA Interference; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection; D024483:Vitamin K 3 / Q000633:toxicity
D004791:Enzyme Inhibitors; D013267:Stilbenes; D024483:Vitamin K 3; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D000077185:Resveratrol