Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran

Cell. 2007 Sep 7;130(5):906-17. doi: 10.1016/j.cell.2007.08.002.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Dimerization
  • Disaccharides / chemistry*
  • Disaccharides / metabolism
  • Disaccharides / pharmacology
  • Fish Proteins / chemistry
  • Hagfishes
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunoglobulin Variable Region / chemistry
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / chemistry*
  • Lipopolysaccharides / metabolism
  • Lymphocyte Antigen 96 / chemistry*
  • Lymphocyte Antigen 96 / genetics
  • Lymphocyte Antigen 96 / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Engineering
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry
  • Structural Homology, Protein
  • Sugar Phosphates / chemistry*
  • Sugar Phosphates / metabolism
  • Sugar Phosphates / pharmacology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / chemistry*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • Disaccharides
  • Fish Proteins
  • Immunoglobulin Variable Region
  • LY96 protein, human
  • Lipopolysaccharides
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • Recombinant Fusion Proteins
  • Sugar Phosphates
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • eritoran

Associated data

  • PDB/2Z62
  • PDB/2Z63
  • PDB/2Z64
  • PDB/2Z65
  • PDB/2Z66