Crystal structure of LIR-2 (ILT4) at 1.8 A: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18

BMC Struct Biol. 2002 Oct 11;2:6. doi: 10.1186/1472-6807-2-6.


Background: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2 (also known as ILT2 and ILT4 respectively) are highly related cell surface receptors that bind a broad range of class I MHC molecules with low (microM) affinities. Expressed on monocytic cells and macrophages, both molecules transmit inhibitory signals after binding ligands. In addition to binding host class I MHC, the LIR-1 molecule, which is also expressed on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2 binds UL18 only weakly (microM KD). To understand how HCMV preferentially targets the more broadly expressed LIR-1 molecule, we determined the crystal structure of a ligand-binding fragment of LIR-2, and compared this to the existing high-resolution crystal structure of LIR-1.

Results: Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and crystallized using streak seeding to optimize the crystal morphology. A data set complete to 1.8 A was collected at 100 K from a single crystal in the P4(1)2(1)2 spacegroup. The structure was solved by molecular replacement, using a search model based on the LIR-1 structure.

Conclusions: The overall structure of LIR-2 D1D2 resembles both LIR-1, and Killer Inhibitory Receptors, in that the A strand in each domain forms hydrogen bonds to both beta sheets, and there is a sharp angle between the two immunoglobulin-like domains. However, differences from LIR-1 are observed in each domain, with two key changes apparent in the ligand-binding domain, D1. The region corresponding to the residue 44-57 helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the KIR structures, involving a shortened 310 helix. Secondly, the predicted UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76-84 loop mainchain is displaced 11 A with respect to LIR-1, and Tyrosine 38 adopts an alternative rotamer conformation. In summary, the structure of LIR-2 has revealed significant differences to LIR-1, including ones that may help to explain the >1000-fold lower affinity of LIR-2 for UL18.

Publication types

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

MeSH terms

  • Antigens, CD / chemistry*
  • Antigens, CD / metabolism
  • Binding Sites
  • Capsid Proteins / chemistry
  • Capsid Proteins / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Leukocyte Immunoglobulin-like Receptor B1
  • Membrane Glycoproteins
  • Models, Molecular*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / metabolism


  • Antigens, CD
  • Capsid Proteins
  • LILRB1 protein, human
  • LILRB2 protein, human
  • Leukocyte Immunoglobulin-like Receptor B1
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • VP23 protein, Human herpesvirus 1