Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor

Nature Immunology volume 4, pages 913–919 (2003)Cite this article

Abstract

Leukocyte immunoglobulin-like receptor 1 (LIR-1), an inhibitory receptor expressed on monocytes, dendritic cells and lymphocytes, regulates cellular function by binding a broad range of classical and nonclassical major histocompatibility complex (MHC) class I molecules, and the human cytomegalovirus MHC class I homolog UL18. Here we describe the 3.4-Å crystal structure of a complex between the LIR-1 D1D2 domains and the MHC class I molecule HLA-A2. LIR-1 contacts the mostly conserved β2-microglobulin and α3 domains of HLA-A2. The LIR-1 binding site comprises residues at the interdomain hinge, and a patch at the D1 tip. The structure shows how LIR-1 recognizes UL18 and diverse MHC class I molecules, and indicates that a similar mode of MHC class I recognition is used by other LIR family members.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall structure of the LIR-1–HLA-A2 complex.
Figure 2: Interaction surfaces used by LIR-1 and HLA-A2.
Figure 3: Amino acid contacts at the LIR-1–MHC class I interface.
Figure 4: Implications of UL18–LIR-1 interaction.
Figure 5: LIR-1–MHC class I interactions at the cell surface.
Figure 6: Comparison of the ligand-binding sites on the structures of KIR2DL1 (ref. 14), LIR-1, and FcαRI (ref. 23).

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Borges, L. & Cosman, D. LIRs/ILTs/MIRs, inhibitory and stimulatory Ig-superfamily receptors expressed in myeloid and lymphoid cells. Cytokine Growth Factor Rev. 11, 209–217 (2000).

    Article  CAS  Google Scholar 

  2. Cella, M., Nakajima, H., Facchetti, F., Hoffmann, T. & Colonna, M. ILT receptors at the interface between lymphoid and myeloid cells. Curr. Top. Microbiol. Immunol. 251, 161–166 (2000).

    CAS  PubMed  Google Scholar 

  3. Colonna, M. et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186, 1809–1818 (1997).

    Article  CAS  Google Scholar 

  4. Cosman, D. et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273–282 (1997).

    Article  CAS  Google Scholar 

  5. Beck, S. & Barrell, B.G. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature 331, 269–272 (1988).

    Article  CAS  Google Scholar 

  6. Browne, H., Smith, G., Beck, S. & Minson, T. A complex between the MHC class I homologue encoded by human cytomegalovirus and β2 microglobulin. Nature 347, 770–772 (1990).

    Article  CAS  Google Scholar 

  7. Fahnestock, M.L. et al. The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides. Immunity 3, 583–590 (1995).

    Article  CAS  Google Scholar 

  8. Chapman, T.L., Heikema, A.P. & Bjorkman, P.J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral MHC homolog UL18. Immunity 11, 603–611 (1999).

    Article  CAS  Google Scholar 

  9. Shiroishi, M. et al. Human inhibitory receptors ILT2 and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc. Natl. Acad. Sci. USA 100, 8856–8861 (2003).

    Article  CAS  Google Scholar 

  10. Natarajan, K., Dimasi, N., Wang, J., Mariuzza, R.A. & Margulies, D.H. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu. Rev. Immunol. 20, 853–885 (2002).

    Article  CAS  Google Scholar 

  11. Chapman, T.L., Heikema, A.P., West, A.P., Jr. & Bjorkman, P.J. Crystal structure and ligand binding properties of the D1D2 region of the inhibitory receptor LIR-1 (ILT2). Immunity 13, 727–736 (2000).

    Article  CAS  Google Scholar 

  12. Madden, D.R., Garboczi, D.N. & Wiley, D.C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell 75, 693–708 (1993).

    Article  CAS  Google Scholar 

  13. Rudolph, M.G. & Wilson, I.A. The specificity of TCR/pMHC interaction. Curr. Opin. Immunol. 14, 52–65 (2002).

    Article  CAS  Google Scholar 

  14. Fan, Q.R., Long, E.O. & Wiley, D.C. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Nat. Immunol. 2, 452–460 (2001).

    Article  CAS  Google Scholar 

  15. Gao, G.F. et al. Crystal structure of the complex between human CD8α(α) and HLA-A2. Nature 387, 630–634 (1997).

    Article  CAS  Google Scholar 

  16. Cosman, D., Fanger, N. & Borges, L. Human cytomegalovirus, MHC class I and inhibitory signalling receptors: more questions than answers. Immunol. Rev. 168, 177–185 (1999).

    Article  CAS  Google Scholar 

  17. Willcox, B.E. et al. Crystal structure of LIR-2 (ILT4) at 1.8 Å: differences from LIR-1 (ILT2) in regions implicated in the binding of the human cytomegalovirus class I MHC homolog UL18. BMC. Struct. Biol. 2, 6 (2002).

    Article  Google Scholar 

  18. Allen, R.L., Raine, T., Haude, A., Trowsdale, J. & Wilson, M.J. Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures. J. Immunol. 167, 5543–5547 (2001).

    Article  CAS  Google Scholar 

  19. van der Merwe, P.A., Davis, S.J., Shaw, A.S. & Dustin, M.L. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin. Immunol. 12, 5–21 (2000).

    Article  CAS  Google Scholar 

  20. Dietrich, J., Cella, M. & Colonna, M. Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J. Immunol. 166, 2514–2521 (2001).

    Article  CAS  Google Scholar 

  21. Young, N.T., Uhrberg, M., Phillips, J.H., Lanier, L.L. & Parham, P. Differential expression of leukocyte receptor complex-encoded Ig-like receptors correlates with the transition from effector to memory CTL. J. Immunol. 166, 3933–3941 (2001).

    Article  CAS  Google Scholar 

  22. Wende, H., Colonna, M., Ziegler, A. & Volz, A. Organization of the leukocyte receptor cluster (LRC) on human chromosome 19q13.4. Mamm. Genome 10, 154–160 (1999).

    Article  CAS  Google Scholar 

  23. Herr, A.B., Ballister, E.R. & Bjorkman, P.J. Insights into mucosal immunity from the structures of human FcaRI and its complex with IgA1-Fc. Nature 423, 614–620 (2003).

    Article  CAS  Google Scholar 

  24. Kubagawa, H., Burrows, P.D. & Cooper, M.D. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl. Acad. Sci. USA 94, 5261–5266 (1997).

    Article  CAS  Google Scholar 

  25. Martin, A.M., Kulski, J.K., Witt, C., Pontarotti, P. & Christiansen, F.T. Leukocyte Ig-like receptor complex (LRC) in mice and men. Trends Immunol. 23, 81–88 (2002).

    Article  CAS  Google Scholar 

  26. Barten, R., Torkar, M., Haude, A., Trowsdale, J. & Wilson, M.J. Divergent and convergent evolution of NK-cell receptors. Trends Immunol. 22, 52–57 (2001).

    Article  CAS  Google Scholar 

  27. Trowsdale, J. Genetic and functional relationships between MHC and NK receptor genes. Immunity 15, 363–374 (2001).

    Article  CAS  Google Scholar 

  28. Garboczi, D.N., Hung, D.T. & Wiley, D.C. HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc. Natl. Acad. Sci. USA 89, 3429–3433 (1992).

    Article  CAS  Google Scholar 

  29. Pace, C.N., Vajdos, F., Fee, L., Grimsley, G. & Gray, T. How to measure and predict the molar absorption coefficient of a protein. Protein Sci. 4, 2411–2423 (1995).

    Article  CAS  Google Scholar 

  30. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  Google Scholar 

  31. Navaza, J. AMORE—an automated package for molecular replacement. Acta Crystallogr. A 50, 157–163 (1994).

    Article  Google Scholar 

  32. CCP4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).

  33. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  34. Brunger, A.T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D. Biol. Crystallogr. 54, 905–921 (1998).

    Article  CAS  Google Scholar 

  35. Su, X.D. et al. Crystal structure of hemolin: a horseshoe shape with implications for homophilic adhesion. Science 281, 991–995 (1998).

    Article  CAS  Google Scholar 

  36. Kraulis, P.J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

  37. Merritt, E.A. & Murphy, M.E.P. Raster3D Version 2.0, a program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994).

    Article  CAS  Google Scholar 

  38. Nicholls, A., Sharp, K.A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281–296 (1991).

    Article  CAS  Google Scholar 

  39. DeLano, W.L. The PyMOL Molecular Graphics System. (DeLano Scientific, San Carlos, California, 2002).

    Google Scholar 

  40. Ding, Y.H. et al. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity 8, 403–411 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Bjorkman laboratory for technical assistance, and C. O'Callaghan and A. van der Merwe for critical reading of the manuscript. B.E.W. was supported by a Wellcome Trust Travelling Fellowship and is now funded by a Medical Research Council Career Development Award.

Author information

Author notes

  1. Benjamin E Willcox

    Present address: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK

Authors and Affiliations

  1. Division of Biology 114-96, California Institute of Technology, Pasadena, 91125, California, USA

    Benjamin E Willcox, Leonard M Thomas & Pamela J Bjorkman

  2. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, 91125, California, USA

    Leonard M Thomas & Pamela J Bjorkman

Authors
  1. Benjamin E Willcox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonard M Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela J Bjorkman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pamela J Bjorkman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1.

Assessment of agreement between the atomic model and the x-ray data. From the top left and working from left to right and top to bottom, the graphs indicate the following: the Wilson plot; optical resolution as a function of the crystallographic resolution; data completeness and structure factor error as a function of the d spacing; maximal and minimal coordinate error dependence on d spacing; a stereographic projection of the averaged radial data structure-factor data completeness; and the R-factor dependence and Luzzati plot with an atomic error = 0.532. All graphs are taken directly from the program SFcheck output1. (PDF 273 kb)

1. Vaguine, A. A., Richelle, J. & Wodak, S. J. SFCHECK: a unified set of procedures for evaluating the quality of macromolecular structure-factor data and their agreement with the atomic model. Acta Crystallogr D Biol Crystallogr 55, 191-205. (1999).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willcox, B., Thomas, L. & Bjorkman, P. Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat Immunol 4, 913–919 (2003). https://doi.org/10.1038/ni961

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni961

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing