Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation

• Published in: Science (American Association for the Advancement of Science) Vol. 371; no. 6524
• Main Authors: Liu, Shixuan, Li, Shuang, Shen, Guomin, Sukumar, Narayanasami, Krezel, Andrzej M, Li, Weikai
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 01.01.2021; American Association for the Advancement of Science (AAAS)
• Subjects: Adducts; Aging (Individuals); Animals; Anticoagulants; Anticoagulants - pharmacology; Binding; Biocatalysis; Bleeding; Blood coagulation; Blood Coagulation - drug effects; Catalysis; Catalytic Domain; Charge transfer; Coordination compounds; Crystal structure; Crystallography, X-Ray; Cysteine; Cysteine - chemistry; Domains; Electron transfer; Electrons; Enzymes; Hemostatics; Homology; Humans; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Integrals; Membranes; Neonates; Organic Chemistry; Oxidation; Oxidation-Reduction; Protein Structure, Secondary; Proteins; Reduction; Substrates; Takifugu; Vitamin K; Vitamin K - antagonists & inhibitors; Vitamin K Epoxide Reductases - chemistry
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abc5667

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.