Structures of the toll-like receptor family and its ligand complexes

Immunity. 2008 Aug 15;29(2):182-91. doi: 10.1016/j.immuni.2008.07.007.


Toll-like receptors (TLRs) play central roles in the innate immune response by recognizing conserved structural patterns in diverse microbial molecules. Here, we discuss ligand binding and activation mechanisms of the TLR family. Hydrophobic ligands of TLR1, TLR2, and TLR4 interact with internal protein pockets. In contrast, dsRNA, a hydrophilic ligand, interacts with the solvent-exposed surface of TLR3. Binding of agonistic ligands, lipopeptides or dsRNA, induces dimerization of the ectodomains of the various TLRs, forming dimers that are strikingly similar in shape. In these "m"-shaped complexes, the C termini of the extracellular domains of the TLRs converge in the middle. This observation suggests the hypothesis that dimerization of the extracellular domains forces the intracellular TIR domains to dimerize, and this initiates signaling by recruiting intracellular adaptor proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Dimerization
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Lipopolysaccharide Receptors / immunology
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Lymphocyte Antigen 96 / immunology
  • Lymphocyte Antigen 96 / metabolism*
  • Protein Structure, Tertiary*
  • Receptors, Interleukin-1 / metabolism
  • Toll-Like Receptors / chemistry*
  • Toll-Like Receptors / metabolism*


  • Ligands
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Receptors, Interleukin-1
  • Toll-Like Receptors