Abstract
TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Cloning, Molecular
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Crystallography, X-Ray
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Dimerization
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Disaccharides / chemistry*
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Disaccharides / metabolism
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Disaccharides / pharmacology
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Fish Proteins / chemistry
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Hagfishes
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Humans
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Hydrophobic and Hydrophilic Interactions
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Immunoglobulin Variable Region / chemistry
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / chemistry*
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Lipopolysaccharides / metabolism
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Lymphocyte Antigen 96 / chemistry*
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Lymphocyte Antigen 96 / genetics
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Lymphocyte Antigen 96 / metabolism
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Mice
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Mutation
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Protein Binding
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Protein Conformation
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Protein Engineering
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Structural Homology, Protein
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Sugar Phosphates / chemistry*
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Sugar Phosphates / metabolism
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Sugar Phosphates / pharmacology
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / chemistry*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
Substances
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Disaccharides
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Fish Proteins
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Immunoglobulin Variable Region
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LY96 protein, human
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Lipopolysaccharides
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Ly96 protein, mouse
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Lymphocyte Antigen 96
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Recombinant Fusion Proteins
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Sugar Phosphates
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TLR4 protein, human
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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eritoran
Associated data
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PDB/2Z62
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PDB/2Z63
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PDB/2Z64
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PDB/2Z65
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PDB/2Z66