Warfarin and vitamin K compete for binding to Phe55 in human VKOR
| Autor: | Katrin J. Czogalla, Veit Hornung, Kerstin Liphardt, Arijit Biswas, Matthias Watzka, Klara Höning, Johannes Oldenburg |
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| Rok vydání: | 2016 |
| Předmět: |
Protein Conformation
alpha-Helical 0301 basic medicine Vitamin Phenylalanine Drug Resistance Plasma protein binding 030204 cardiovascular system & hematology Pharmacology Biology Reductase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Structural Biology Catalytic Domain Vitamin K Epoxide Reductases medicine Humans Binding site Molecular Biology Vitamin K2 HEK 293 cells Warfarin Vitamin K 2 Vitamin K 1 Molecular Docking Simulation HEK293 Cells 030104 developmental biology chemistry Biocatalysis Vitamin K epoxide reductase Oxidation-Reduction Protein Binding medicine.drug |
| Zdroj: | Nature Structural & Molecular Biology. 24:77-85 |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | Vitamin K epoxide reductase (VKOR) catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain γ-carboxylation of vitamin K-dependent proteins. VKOR is also a therapeutic target of warfarin, a treatment for thrombotic disorders. However, the structural and functional basis of vitamin K reduction and the antagonism of warfarin inhibition remain elusive. Here, we identified putative binding sites of both K vitamers and warfarin on human VKOR. The predicted warfarin-binding site was verified by shifted dose-response curves of specified mutated residues. We used CRISPR-Cas9-engineered HEK 293T cells to assess the vitamin K quinone and vitamin K 2,3-epoxide reductase activities of VKOR variants to characterize the vitamin K naphthoquinone head- and isoprenoid side chain-binding regions. Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. |
| Databáze: | OpenAIRE |
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