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Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer.

Liu S, Cheng W, Fowle Grider R, Shen G, Li W
Nat Commun 5 3110 (2014)
Related entries: 4nv5, 4nv6

Cited: 25 times
EuropePMC logo PMID: 24477003

Abstract

The intramembrane vitamin K epoxide reductase (VKOR) supports blood coagulation in humans and is the target of the anticoagulant warfarin. VKOR and its homologues generate disulphide bonds in organisms ranging from bacteria to humans. Here, to better understand the mechanism of VKOR catalysis, we report two crystal structures of a bacterial VKOR captured in different reaction states. These structures reveal a short helix at the hydrophobic active site of VKOR that alters between wound and unwound conformations. Motions of this 'horizontal helix' promote electron transfer by regulating the positions of two cysteines in an adjacent loop. Winding of the helix separates these 'loop cysteines' to prevent backward electron flow. Despite these motions, hydrophobicity at the active site is maintained to facilitate VKOR catalysis. Biochemical experiments suggest that several warfarin-resistant mutations act by changing the conformation of the horizontal helix. Taken together, these studies provide a comprehensive understanding of VKOR function.

Articles - 4nv2 mentioned but not cited (4)

  1. Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer. Liu S, Cheng W, Fowle Grider R, Shen G, Li W. Nat Commun 5 3110 (2014)
  2. Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer. Shen G, Cui W, Zhang H, Zhou F, Huang W, Liu Q, Yang Y, Li S, Bowman GR, Sadler JE, Gross ML, Li W. Nat. Struct. Mol. Biol. 24 69-76 (2017)
  3. Intramembrane Thiol Oxidoreductases: Evolutionary Convergence and Structural Controversy. Li S, Shen G, Li W. Biochemistry 57 258-266 (2018)
  4. Investigations on 2-(4-Cyanophenylamino) acetic acid by FT-IR,FT-Raman, NMR and UV-Vis spectroscopy, DFT (NBO, HOMO-LUMO, MEP and Fukui function) and molecular docking studies. Rahuman MH, Muthu S, Raajaraman BR, Raja M, Umamahesvari H. Heliyon 6 e04976 (2020)


Reviews citing this publication (6)

  1. Chemistry and Enzymology of Disulfide Cross-Linking in Proteins. Fass D, Thorpe C. Chem. Rev. 118 1169-1198 (2018)
  2. Structural Modeling Insights into Human VKORC1 Phenotypes. Czogalla KJ, Watzka M, Oldenburg J. Nutrients 7 6837-6851 (2015)
  3. Membrane properties that shape the evolution of membrane enzymes. Sanders CR, Hutchison JM. Curr. Opin. Struct. Biol. 51 80-91 (2018)
  4. Structural basis for catalysis at the membrane-water interface. Dufrisne MB, Petrou VI, Clarke OB, Mancia F. Biochim Biophys Acta Mol Cell Biol Lipids 1862 1368-1385 (2017)
  5. Oxidative protein folding: state-of-the-art and current avenues of research in plants. Meyer AJ, Riemer J, Rouhier N. New Phytol. 221 1230-1246 (2019)
  6. VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues. Lacombe J, Ferron M. Nutrients 10 (2018)

Articles citing this publication (15)

  1. Warfarin and vitamin K compete for binding to Phe55 in human VKOR. Czogalla KJ, Biswas A, Höning K, Hornung V, Liphardt K, Watzka M, Oldenburg J. Nat. Struct. Mol. Biol. 24 77-85 (2017)
  2. Enzyme structure captures four cysteines aligned for disulfide relay. Gat Y, Vardi-Kilshtain A, Grossman I, Major DT, Fass D. Protein Sci. 23 1102-1112 (2014)
  3. Evidence of a target resistance to antivitamin K rodenticides in the roof rat Rattus rattus: identification and characterisation of a novel Y25F mutation in the Vkorc1 gene. Goulois J, Chapuzet A, Lambert V, Chatron N, Tchertanov L, Legros L, Benoît E, Lattard V. Pest Manag. Sci. 72 544-550 (2016)
  4. Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family. Bevans CG, Krettler C, Reinhart C, Watzka M, Oldenburg J. Nutrients 7 6224-6249 (2015)
  5. Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation. Liu S, Li S, Shen G, Sukumar N, Krezel AM, Li W. Science 371 eabc5667 (2021)
  6. Membrane Protein Structure in Live Cells: Methodology for Studying Drug Interaction by Mass Spectrometry-Based Footprinting. Shen G, Li S, Cui W, Liu S, Yang Y, Gross M, Li W. Biochemistry 57 286-294 (2018)
  7. Stabilization of warfarin-binding pocket of VKORC1 and VKORL1 by a peripheral region determines their different sensitivity to warfarin inhibition. Shen G, Li S, Cui W, Liu S, Liu Q, Yang Y, Gross M, Li W. J. Thromb. Haemost. 16 1164-1175 (2018)
  8. Characterization of Warfarin Inhibition Kinetics Requires Stabilization of Intramembrane Vitamin K Epoxide Reductases. Li S, Liu S, Yang Y, Li W. J Mol Biol 432 5197-5208 (2020)
  9. Distinct enzymatic strategies for de novo generation of disulfide bonds in membranes. Li W. Crit Rev Biochem Mol Biol 58 36-49 (2023)
  10. Low warfarin resistance frequency in Norway rats in two cities in China after 30 years of usage of anticoagulant rodenticides. Ma X, Wang D, Li N, Liu L, Tian L, Luo C, Cong L, Feng Z, Liu XH, Song Y. Pest Manag. Sci. 74 2555-2560 (2018)
  11. Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact. Chiasson MA, Rollins NJ, Stephany JJ, Sitko KA, Matreyek KA, Verby M, Sun S, Roth FP, DeSloover D, Marks DS, Rettie AE, Fowler DM. Elife 9 (2020)
  12. New pieces to an old puzzle: identifying the warfarin-binding site that prevents clotting. Hilton JK, Van Horn WD. Nat. Struct. Mol. Biol. 24 5-6 (2017)
  13. Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1. Chatron N, Hammed A, Benoît E, Lattard V. Nutrients 11 (2019)
  14. Structural features determining the vitamin K epoxide reduction activity in the VKOR family of membrane oxidoreductases. Shen G, Li C, Cao Q, Megta AK, Li S, Gao M, Liu H, Shen Y, Chen Y, Yu H, Li S, Li W. FEBS J 289 4564-4579 (2022)
  15. The catalytic mechanism of vitamin K epoxide reduction in a cellular environment. Shen G, Cui W, Cao Q, Gao M, Liu H, Su G, Gross ML, Li W. J Biol Chem 296 100145 (2021)


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