Crystal structure of HLA-G: A nonclassical MHC class I molecule expressed at the fetal-maternal interface

Craig S. Clements, Lars Kjer-Nielsen, Lyudmila Kostenko, Hilary L. Hoare, Michelle A. Dunstone, Eric Moses, Katy Freed, Andrew G. Brooks, Jamie Rossjohn, James McCluskey

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


HLA-G is a nonclassical major histocompatibility complex class I (MHC-I) molecule that is primarily expressed at the fetal-maternal interface, where it is thought to play a role in protecting the fetus from the maternal immune response. HLA-G binds a limited repertoire of peptides and interacts with the inhibitory leukocyte Ig-like receptors LIR-1 and LIR-2 and possibly with certain natural killer cell receptors. To gain further insights into HLA-G function, we determined the 1.9-Å structure of a monomeric HLA-G complexed to a natural endogenous peptide ligand from histone H2A (RIIPRHLQL). An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G. The α3 domain of HLA-G, a candidate binding site for the LIR-1 and -2 inhibitory receptors, is structurally distinct from the α3 domains of classical MHC-I molecules, providing a rationale for the observed affinity differences for these ligands. The structural data suggest a head-to-tail mode of dimerization, mediated by an intermolecular disulfide bond, that is consistent with the observation of HLA-G dimers on the cell surface.

Original languageEnglish (US)
Pages (from-to)3360-3365
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - Mar 1 2005
Externally publishedYes


  • Crystallography
  • Immunoreceptor
  • Leukocyte Ig-like receptor recognition
  • Materno-fetal tolerance

ASJC Scopus subject areas

  • General


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