Journal
SCIENCE
Volume 371, Issue 6524, Pages 43-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc5667
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Funding
- National Heart, Lung, and Blood Institute (NHLBI) [R01 HL121718]
- W. M. Keck Foundation (Forefront of Science Award)
- Children's Discovery Institute [MCII 2020-854]
- National Eye Institute (NEI) [R21 EY028705]
- National Institute of General Medical Sciences (NIGMS) [R01 GM131008]
- NIGMS [P30 GM124165]
- NIH-ORIP [HEI S10OD021527]
- U.S. Department of Energy (DOE) [DE-AC02-06CH11357]
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Vitamin K antagonists act by mimicking key interactions and conformational changes required for the VKOR catalytic cycle, which is crucial for their anticoagulant effect.
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 hydrogen-bonding 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.
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