Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran
Copyright policy )Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran
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.
- Chonnam National University Korea (Republic of)
- Korea Advanced Institute of Science and Technology Korea (Republic of)
- Korean Association Of Science and Technology Studies Korea (Republic of)
- National University of Mongolia Mongolia
- Sapporo Medical University Japan
Fish Proteins, Lipopolysaccharides, Models, Molecular, 572, PROTEINS, BACTERIAL LIPOPOLYSACCHARIDE, Molecular Sequence Data, Immunoglobulin Variable Region, Lymphocyte Antigen 96, Crystallography, X-Ray, Disaccharides, PROTEIN COMPLEXES, Mice, MONOMERIC ENDOTOXIN, Animals, Humans, CELL ACTIVATION, TLR4, Amino Acid Sequence, Cloning, Molecular, MOLIMMUNO, TOLL-LIKE RECEPTORS, LEUCINE-RICH REPEAT, Binding Sites, Molecular Structure, Biochemistry, Genetics and Molecular Biology(all), CONFERS LIPOPOLYSACCHARIDE RESPONSIVENESS, LIPID IVA, Mutation, MD-2 BINDS, Hagfishes, Dimerization, Hydrophobic and Hydrophilic Interactions, Protein Binding
Fish Proteins, Lipopolysaccharides, Models, Molecular, 572, PROTEINS, BACTERIAL LIPOPOLYSACCHARIDE, Molecular Sequence Data, Immunoglobulin Variable Region, Lymphocyte Antigen 96, Crystallography, X-Ray, Disaccharides, PROTEIN COMPLEXES, Mice, MONOMERIC ENDOTOXIN, Animals, Humans, CELL ACTIVATION, TLR4, Amino Acid Sequence, Cloning, Molecular, MOLIMMUNO, TOLL-LIKE RECEPTORS, LEUCINE-RICH REPEAT, Binding Sites, Molecular Structure, Biochemistry, Genetics and Molecular Biology(all), CONFERS LIPOPOLYSACCHARIDE RESPONSIVENESS, LIPID IVA, Mutation, MD-2 BINDS, Hagfishes, Dimerization, Hydrophobic and Hydrophilic Interactions, Protein Binding
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