Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation

Shixuan Liu, Shuang Li, Guomin Shen, Narayanasami Sukumar, Andrzej M. Krezel, Weikai Li

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Vitamin K antagonists are widely used anticoagulants that target vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, we report 11 x-ray crystal structures of human VKOR and pufferfish VKOR-like, with substrates and antagonists in different redox states. Substrates entering the active site in a partially oxidized state form cysteine adducts that induce an open-to-closed conformational change, triggering reduction. Binding and catalysis are facilitated by hydrogen-bonding interactions in a hydrophobic pocket. The antagonists bind specifically to the same hydrogenbonding residues and induce a similar closed conformation. Thus, vitamin K antagonists act through mimicking the key interactions and conformational changes required for the VKOR catalytic cycle.

Original languageEnglish
Article numbereabc5667
Issue number6524
StatePublished - Jan 1 2021


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