6WV6

Human VKOR with phenindione

Summary for 6WV6

• Entry DOI: 10.2210/pdb6wv6/pdb
• Descriptor: Vitamin K epoxide reductase, termini restrained by green fluorescent protein, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, Phenindione, ... (4 entities in total)
• Functional Keywords: vitamin k epoxide reductase (vkor), vitamin k, warfarin, superwarfarin, phenindione, vitamin k expoxide(ko), membrane protein, oxidoreductase, fluorescent protein
• Biological source: Aequorea victoria (Jellyfish); More
• Total number of polymer chains: 1
• Total formula weight: 45132.75

Authors

Liu, S.,Sukumar, N.,Li, W. (deposition date: 2020-05-05, release date: 2020-11-11, Last modification date: 2024-11-06)

Primary citation

Liu, S.,Li, S.,Shen, G.,Sukumar, N.,Krezel, A.M.,Li, W.
Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.
Science, 371:-, 2021

PubMed Abstract: 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.

PubMed: 33154105
DOI: 10.1126/science.abc5667

Experimental method

X-RAY DIFFRACTION (2.7 Å)