4z3d
From Proteopedia
Human carbonyl reductase 1 with glutathione in a protective configuration
Structural highlights
FunctionCBR1_HUMAN NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.[1] [2] [3] [4] Publication Abstract from PubMedThe NADPH-dependent human carbonyl reductase 1 (hCBR1), a member of the short-chain dehydrogenase/reductase protein family, plays an important role in the ubiquitous metabolism of endogenous and xenobiotic carbonyl containing compounds. Glutathione (GSH) is also a cofactor of hCBR1, however, its role in the carbonyl reductase function of the enzyme is still unclear. In this study, we presented the crystal structure of hCBR1 in complex with GSH, in the absence of its substrates or inhibitors. Interestingly, we found that the GSH molecule presents in a configuration quite different from that was previously reported when substrate is binding to hCBR1. Our structure indicates that GSH contributes to the substrate selectivity of hCBR1 and protects the catalytic center of hCBR1 through a switch-like mechanism. The isothermal titration calorimetry and enzymology data shows that GSH directly binding with hCBR1 when there's no substrate exist. The enzymology data also shows GSH protects NADPH being attacked by oxidative small molecules. This is the first time that GSH is found to demonstrate such functions as a co-enzyme. Our crystal structure succeeds in providing critical insights into the substrate selectivity of hCBR1 and the interaction between hCBR1 and GSH. Structural insights on the catalytic site protection of human carbonyl reductase 1 by glutathione.,Liang Q, Liu R, Du S, Ding Y J Struct Biol. 2015 Oct;192(1):138-44. doi: 10.1016/j.jsb.2015.09.005. Epub 2015 , Sep 14. PMID:26381805[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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