| From agonist to antagonist: structure and dynamics of innate immune glycoprotein MD-2 upon recognition of variably acylated bacterial endotoxins. | |
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MedLine Citation:
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PMID: 21924775 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The human immune response to an infection by Gram-negative bacteria involves detection of lipopolysaccharides (LPS), also known as endotoxins, which comprise the bacterial outer cell wall. Distinct from mammalian glycolipid structures, LPS have a conserved chemical pattern that is recognized by the pattern recognition receptor complex formed by myeloid differentiation protein 2 (MD-2) and toll-like receptor 4 (TLR4). A remarkable immune-mediated structure-toxicity relationship has been defined that relates to the number of acyl chains in the endotoxin. While there is a clear correlation between endotoxin acylation and elicited agonist or antagonist responses, the 3D structural basis of this relationship remains unclear. In order to explore, at atomic-resolution, the effects of a range of chemically distinct endotoxins on the structure and dynamics of their MD-2·endotoxin complexes, we examined a series of variably acylated lipid A molecules from Escherichia coli and Neisseria meningitidis in complex with human MD-2. Through the application of molecular dynamics simulations, in concert with experimental data, we have identified specific structural and dynamic features of the MD-2-endotoxin complexes that may control dimerization of TLR4 molecules. As dimerization is central to the release of downstream chemical mediators, the results provide a structural foundation for the ability of endotoxins to act as either agonists or antagonists of the TLR4 pathway. |
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Authors:
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Mari L DeMarco; Robert J Woods |
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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: 2011-09-16 |
Journal Detail:
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Title: Molecular immunology Volume: 49 ISSN: 1872-9142 ISO Abbreviation: Mol. Immunol. Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-31 Completed Date: 2011-12-20 Revised Date: 2012-01-06 |
Medline Journal Info:
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Nlm Unique ID: 7905289 Medline TA: Mol Immunol Country: England |
Other Details:
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Languages: eng Pagination: 124-33 Citation Subset: IM |
Copyright Information:
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Published by Elsevier Ltd. |
Affiliation:
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Complex Carbohydrate Research Center, University of Georgia, GA 30602, USA. mdemarco@wustl.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acylation Humans Immunity, Innate / immunology Lipid A / chemistry*, immunology*, metabolism Lymphocyte Antigen 96 / chemistry*, immunology*, metabolism Models, Molecular Protein Structure, Quaternary Protein Structure, Secondary Protein Structure, Tertiary Toll-Like Receptor 4 / chemistry*, immunology, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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5R01GM055230/GM/NIGMS NIH HHS; P41 RR005351-15/RR/NCRR NIH HHS; RR05351/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/LY96 protein, human; 0/Lipid A; 0/Lymphocyte Antigen 96; 0/TLR4 protein, human; 0/Toll-Like Receptor 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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