ArticleNature structural & molecular biology2017
Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer.
Article in Nature structural & molecular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 75 citations in OpenAlex.
- Optimized Digestion Conditions for Membrane Protein Footprinting and Mass Spectrometry Analysis.Membranes · 2026Article
- Structural disruption of VKORC1 by resistance mutations reveals a conserved hydrophobic pattern essential for warfarin binding: insights from molecular dynamics analyses.Molecular diversity · 2026Article
- Isomer-Dependent Pharmacokinetic Behavior and VKOR Interactions of Second-Generation Anticoagulant Rodenticides: An Integrated In Vivo-In Vitro-In Silico Investigation.International journal of molecular sciences · 2026Article
- Small-molecule inhibition of γ-glutamyl carboxylase reveals a novel anticoagulant strategy.Blood advances · 2026Article
- New polymorphisms of Vkork1 gene related to anticoagulant resistance of rats and mice in Italy.Pest management science · 2025Article
- Article
- In Vitro Evaluation of Novel Furo[3,2-Molecules (Basel, Switzerland) · 2025Article
- Mass Spectrometry-Based Protein Footprinting for Protein Structure Characterization.Accounts of chemical research · 2025Article
- Multimodal mechanisms of pathogenic variants in the signal peptide of FIX leading to hemophilia B.Blood advances · 2024Article
- Evaluating Chemical Footprinting-Induced Perturbation of Protein Higher Order Structure.Analytical chemistry · 2024Article
- Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.The Journal of biological chemistry · 2024Article
- Molecular basis of inherited protein C deficiency results from genetic variations in the signal peptide and propeptide regions.Journal of thrombosis and haemostasis : JTH · 2023Article
- Workflow for Validating Specific Amino Acid Footprinting Reagents for Protein Higher Order Structure Elucidation.Analytical chemistry · 2023Article
- Vitamin K-dependent carboxylation regulates CaCell reports · 2023Article
- Missense VKOR mutants exhibit severe warfarin resistance but lack VKCFD via shifting to an aberrantly reduced state.Blood advances · 2023Article
- Distinct enzymatic strategies forCritical reviews in biochemistry and molecular biology · 2023Article
- Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene.Frontiers in pharmacology · 2023Article
- Structural features determining the vitamin K epoxide reduction activity in the VKOR family of membrane oxidoreductases.The FEBS journal · 2022Article
- Development of a sandwich enzyme-linked immunosorbent assay (ELISA) to quantify γ-glutamyl-carboxylated clotting factor IX and assess redox susceptibility of anticoagulant chemicals.The Journal of veterinary medical science · 2022Article
- Characterizing Endogenous Protein Complexes with Biological Mass Spectrometry.Chemical reviews · 2022Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we conducted structure simulations, which revealed a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.