Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 1, Pages 77-85Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3338
Keywords
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Funding
- BONFOR [2015-1-01]
- Baxter Germany, GmbH
- Deutsche Forschungsgemeinschaft (DFG) [Ol100 5-1]
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Vitamin K epoxide reductase (VKOR) catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain gamma-carboxylation of vitamin K-dependent proteins. VKOR is also a therapeutic target of warfarin, a treatment for thrombotic disorders. However, the structural and functional basis of vitamin K reduction and the antagonism of warfarin inhibition remain elusive. Here, we identified putative binding sites of both K vitamers and warfarin on human VKOR. The predicted warfarin-binding site was verified by shifted dose-response curves of specified mutated residues. We used CRISPR-Cas9-engineered HEK 293T cells to assess the vitamin K quinone and vitamin K 2,3-epoxide reductase activities of VKOR variants to characterize the vitamin K naphthoquinone head- and isoprenoid side chain-binding regions. Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor.
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