ArticleBlood advances2023
Missense VKOR mutants exhibit severe warfarin resistance but lack VKCFD via shifting to an aberrantly reduced state.
Article in Blood advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 6 citations in OpenAlex.
- Structural disruption of VKORC1 by resistance mutations reveals a conserved hydrophobic pattern essential for warfarin binding: insights from molecular dynamics analyses.Molecular diversity · 2026Article
- Recent Advances in Mass Spectrometry-Based Bottom-Up Proteomics.Analytical chemistry · 2025Review
- A Chinese patient with cardiogenic stroke and warfarin resistance: a case report.BMC neurology · 2025Article
- Synergy of Mutation-Induced Effects in Human Vitamin K Epoxide Reductase: Perspectives and Challenges for Allo-Network Modulator Design.International journal of molecular sciences · 2024Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Missense vitamin K epoxide reductase (VKOR) mutations in patients cause resistance to warfarin treatment but not abnormal bleeding due to defective VKOR activity. The underlying mechanism of these phenotypes remains unknown. Here we show that the redox state of these mutants is essential to their activity and warfarin resistance. Using a mass spectrometry-based footprinting method, we found that severe warfarin-resistant mutations change the VKOR active site to an aberrantly reduced state in cells. Molecular dynamics simulation based on our recent crystal structures of VKOR reveals that these mutations induce an artificial opening of the protein conformation that increases access of small molecules, enabling them to reduce the active site and generating constitutive activity uninhibited by warfarin. Increased activity also compensates for the weakened substrate binding caused by these mutations, thereby maintaining normal VKOR function. The uninhibited nature of severe resistance mutations suggests that patients showing signs of such mutations should be treated by alternative anticoagulation strategies.
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