Crystal structure of soluble MD-1 and its interaction with lipid IVa

Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10990-5. doi: 10.1073/pnas.1004153107. Epub 2010 Jun 1.


Lipopolysaccharide (LPS) of Gram-negative bacteria is a common pathogen-associated molecular pattern (PAMP) that induces potent innate immune responses. The host immune response against LPS is triggered by myeloid differentiation factor 2 (MD-2) in association with Toll-like receptor 4 (TLR4) on the cell surface. The MD-2/TLR4-mediated LPS response is regulated by the evolutionarily related complex of MD-1 and Toll-like receptor homolog RP105. Here, we report crystallographic and biophysical data that demonstrate a previously unidentified direct interaction of MD-1 with LPS. The crystal structure of chicken MD-1 (cMD-1) at 2.0 A resolution exhibits a beta-cup-like fold, similar to MD-2, that encloses a hydrophobic cavity between the two beta-sheets. A lipid-like moiety was observed inside the cavity, suggesting the possibility of a direct MD-1/LPS interaction. LPS was subsequently identified as an MD-1 ligand by native gel electrophoresis and gel filtration analyses. The crystal structure of cMD-1 with lipid IVa, an LPS precursor, at 2.4 A resolution revealed that the lipid inserts into the deep hydrophobic cavity of the beta-cup-like structure, but with some important differences compared with MD-2. These findings suggest that soluble MD-1 alone, in addition to its complex with RP105, can regulate host LPS sensitivity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Surface / chemistry*
  • Antigens, Surface / genetics
  • Avian Proteins / chemistry*
  • Avian Proteins / genetics
  • Avian Proteins / immunology
  • Binding Sites
  • Chickens / genetics
  • Chickens / immunology
  • Crystallography, X-Ray
  • Glycolipids / chemistry*
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Lipid A / analogs & derivatives*
  • Lipid A / chemistry
  • Lymphocyte Antigen 96 / chemistry
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Sequence Homology, Amino Acid
  • Solubility
  • Toll-Like Receptor 4 / chemistry


  • Antigens, Surface
  • Avian Proteins
  • Glycolipids
  • Ligands
  • Lipid A
  • Lymphocyte Antigen 96
  • Macromolecular Substances
  • Recombinant Proteins
  • Toll-Like Receptor 4
  • lipid A precursors, bacterial

Associated data

  • PDB/3MTX
  • PDB/3MU3