| Biochemical, structural and molecular dynamics analyses of the potential virulence factor RipA from Yersinia pestis. | |
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MedLine Citation:
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PMID: 21966419 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. Yersinia pestis, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel rip (required for intracellular proliferation) operon (ripA, ripB and ripC) is essential for replication and survival of Y. pestis in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the rip operon is conserved among a distally related subset of macrophage-residing pathogens, including Burkholderia and Salmonella species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is ripA, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the rip operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of Y. pestis RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway. |
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Authors:
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Rodrigo Torres; Robert V Swift; Nicholas Chim; Nicole Wheatley; Benson Lan; Brian R Atwood; Céline Pujol; Banu Sankaran; James B Bliska; Rommie E Amaro; Celia W Goulding |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-09-26 |
Journal Detail:
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Title: PloS one Volume: 6 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2011 |
Date Detail:
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Created Date: 2011-10-03 Completed Date: 2012-02-10 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e25084 Citation Subset: IM |
Affiliation:
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Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, United States of America. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Bacterial Proteins / chemistry*, genetics, metabolism* Catalytic Domain Coenzyme A-Transferases / chemistry, genetics, metabolism Crystallography, X-Ray Molecular Dynamics Simulation Molecular Sequence Data Operon / genetics Protein Structure, Secondary Sequence Homology, Amino Acid Static Electricity Virulence Factors / chemistry*, genetics, metabolism* Yersinia pestis / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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1-DP2-OD007237/OD/NIH HHS; AI-65359/AI/NIAID NIH HHS; AI055621/AI/NIAID NIH HHS; U54-AI057158/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Proteins; 0/Virulence Factors; EC 2.8.3.-/4-hydroxybutyrate CoA-transferase; EC 2.8.3.-/Coenzyme A-Transferases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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