An unusual dimeric structure and assembly for TLR4 regulator RP105-MD-1

Nat Struct Mol Biol. 2011 Aug 21;18(9):1028-35. doi: 10.1038/nsmb.2106.


RP105-MD-1 modulates the TLR4-MD-2-mediated, innate immune response against bacterial lipopolysaccharide (LPS). The crystal structure of the bovine 1:1 RP105-MD-1 complex bound to a putative endogenous lipid at 2.9 Å resolution shares a similar overall architecture to its homolog TLR4-MD-2 but assembles into an unusual 2:2 homodimer that differs from any other known TLR-ligand assembly. The homodimer is assembled in a head-to-head orientation that juxtaposes the N-terminal leucine-rich repeats (LRRs) of the two RP105 chains, rather than the usual tail-to-tail configuration of C-terminal LRRs in ligand-activated TLR dimers, such as TLR1-TRL2, TLR2-TLR6, TLR3-TLR3 and TLR4-TLR4. Another unusual interaction is mediated by an RP105-specific asparagine-linked glycan, which wedges MD-1 into the co-receptor binding concavity on RP105. This unique mode of assembly represents a new paradigm for TLR complexes and suggests a molecular mechanism for regulating LPS responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / chemistry*
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antigens, Surface / chemistry*
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Binding Sites
  • Cattle
  • Dimerization
  • Humans
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Models, Molecular
  • Protein Structure, Tertiary
  • Toll-Like Receptor 4 / metabolism*
  • X-Ray Diffraction


  • Antigens, CD
  • Antigens, Surface
  • CD180 protein, human
  • LY86 protein, human
  • Ly78 protein, mouse
  • Ly86 protein, mouse
  • Membrane Glycoproteins
  • Toll-Like Receptor 4

Associated data

  • PDB/3RG1