Katrin J Czogalla, Arijit Biswas, Klara Höning, Veit Hornung, Kerstin Liphardt, Matthias Watzka, Johannes Oldenburg
Nature structural & molecular biology 2017 JanVitamin K epoxide reductase (VKOR) catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain γ-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.
Katrin J Czogalla, Arijit Biswas, Klara Höning, Veit Hornung, Kerstin Liphardt, Matthias Watzka, Johannes Oldenburg. Warfarin and vitamin K compete for binding to Phe55 in human VKOR. Nature structural & molecular biology. 2017 Jan;24(1):77-85
PMID: 27941861
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