Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.

Publication Type:

Journal Article

Source:

Science (2020)

Abstract:

<p>Vitamin K antagonists are widely used anticoagulants targeting vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, here we report eleven 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 a cysteine adduct that induces an open-to-closed conformational change, triggering reduction. Binding and catalysis is 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.</p>

PDB: 
6WV3 (HsVKOR-warfarin), 6WV6 (HsVKOR-phenindione), 6WVH (HsVKOR-Brodifacoum), 6WV7 (HsVKOR-Chlorophacinone), 6WV4 (HsVKOR Cys43Ser-warfarin), 6WV5 (HsVKOR Cys43Ser-KO), 6WVI (TrVKORL), 6WVB (TrVKORL-warfarin), 6WV9 (TrVKORL-K), 6WVA (TrVKORL-KO), and 6WV8 (TrVKORL ‘Cys132Ser’-K)
Detector: 
PILATUS
EIGER
Beamline: 
24-ID-C
24-ID-E
6WV3