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Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer
The intramembrane vitamin K epoxide reductase (VKOR) supports blood coagulation in humans and is the target of the anticoagulant warfarin. VKOR and its homologs generate disulfide bonds in organisms ranging from bacteria to humans. Here, to better understand the mechanism of VKOR catalysis, we repor...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360977/ https://www.ncbi.nlm.nih.gov/pubmed/24477003 http://dx.doi.org/10.1038/ncomms4110 |
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author | Liu, Shixuan Cheng, Wei Grider, Ronald Fowle Shen, Guomin Li, Weikai |
author_facet | Liu, Shixuan Cheng, Wei Grider, Ronald Fowle Shen, Guomin Li, Weikai |
author_sort | Liu, Shixuan |
collection | PubMed |
description | The intramembrane vitamin K epoxide reductase (VKOR) supports blood coagulation in humans and is the target of the anticoagulant warfarin. VKOR and its homologs generate disulfide 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. |
format | Online Article Text |
id | pubmed-4360977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-43609772015-03-16 Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer Liu, Shixuan Cheng, Wei Grider, Ronald Fowle Shen, Guomin Li, Weikai Nat Commun Article The intramembrane vitamin K epoxide reductase (VKOR) supports blood coagulation in humans and is the target of the anticoagulant warfarin. VKOR and its homologs generate disulfide 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. 2014 /pmc/articles/PMC4360977/ /pubmed/24477003 http://dx.doi.org/10.1038/ncomms4110 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Liu, Shixuan Cheng, Wei Grider, Ronald Fowle Shen, Guomin Li, Weikai Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title_full | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title_fullStr | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title_full_unstemmed | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title_short | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer |
title_sort | structures of an intramembrane vitamin k epoxide reductase homolog reveal control mechanisms for electron transfer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360977/ https://www.ncbi.nlm.nih.gov/pubmed/24477003 http://dx.doi.org/10.1038/ncomms4110 |
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