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.

Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1–HLA-Cw4 complex

Abstract

Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4. The KIR2DL1–HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DL1 that hosts the Lys80 residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DL1–HLA-Cw4 and in a previously reported KIR2DL2–HLA-Cw3 complex. A dimeric aggregate of KIR–HLA-C complexes was observed in one KIR2DL1–HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee KIRs with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by KIRs.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Ribbon diagram of the crystal structure of KIR2DL1 bound to HLA-Cw4.
Figure 2: Recognition of HLA-Cw4 by KIR2DL1.
Figure 3: The interactions at the KIR2DL1–HLA-Cw4 interface.
Figure 4: The KIR2DL1 specificity pocket for Lys80 of HLA-Cw4.
Figure 5: Different peptide conformations in HLA-Cw4 and HLA-Cw3.
Figure 6: A common HLA-C binding mode for KIR2DL1 and KIR2DL2.
Figure 7: Ribbon diagram of a crystallographic dimer of the KIR2DL1–HLA-Cw4 complex.

Similar content being viewed by others

References

  1. Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: Function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

    Article  CAS  Google Scholar 

  2. Scharton-Kersten, T. M. & Sher, A. Role of natural killer cells in innate resistance to protozoan infections. Curr. Opin. Immunol. 9, 44–51 (1997).

    Article  CAS  Google Scholar 

  3. Lanier, L. L. NK cell receptors. Annu. Rev. Immunol. 16, 359–393 (1998).

    Article  CAS  Google Scholar 

  4. Khakoo, S. I. et al. Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 12, 687–698 (2000).

    Article  CAS  Google Scholar 

  5. Yokoyama, W. M. in Fundamental Immunology. (ed. Paul, W.E.) 575–603 (Lippincott-Raven, Philadelphia, 1999).

    Google Scholar 

  6. Westgaard, I. H., Berg, S. F., Orstavik, S., Fossum, S. & Dissen, E. Identification of a human member of the Ly-49 multigene family. Eur. J. Immunol. 28, 1839–1846 (1998).

    Article  CAS  Google Scholar 

  7. Barten, R. & Trowsdale, J. The human Ly-49L gene. Immunogenetics 49, 731–734 (1999).

    Article  CAS  Google Scholar 

  8. Long, E. O. & Wagtmann, N. Natural killer cell receptors. Curr. Opin. Immunol. 9, 344–350 (1997).

    Article  CAS  Google Scholar 

  9. Sibley, C. G., Comstock, J. A. & Ahlquist, J. E. DNA hybridization evidence of hominoid phylogeny: a reanalysis of the data. J. Mol. Evol. 30, 202–236 (1990).

    Article  CAS  Google Scholar 

  10. Colonna, M., Borsellino, G., Falco, M., Ferrara, G. B. & Strominger, J. L. HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proc. Natl Acad. Sci. USA 90, 12000–12004 (1993).

    Article  CAS  Google Scholar 

  11. Moretta, A. et al. p58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells: anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J. Exp. Med. 178, 597–604 (1993).

    Article  CAS  Google Scholar 

  12. Colonna, M. & Samaridis, J. Cloning of Ig-superfamily members associated with HLA-C and HLA-B recognition by human NK cells. Science 268, 405–408 (1995).

    Article  CAS  Google Scholar 

  13. Wagtmann, N. et al. Molecular clones of the p58 natural killer cell receptor reveal Ig-related molecules with diversity in both the extra- and intracellular domains. Immunity 2, 439–449 (1995).

    Article  CAS  Google Scholar 

  14. Mandelboim, O. et al. Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. J. Exp. Med. 184, 913–922 (1996).

    Article  CAS  Google Scholar 

  15. Winter, C. C. & Long, E. O. A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. J. Immunol. 158, 4026–4028 (1997).

    CAS  PubMed  Google Scholar 

  16. Boyington, J. C., Motyka, S. A., Schuck, P., Brooks, A. G. & Sun, P. D. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 (2000).

    Article  CAS  Google Scholar 

  17. Fan, Q. R. et al. Direct binding of a soluble natural killer cell inhibitory receptor to a soluble human leukocyte antigen-Cw4 class I major histocompatibility complex molecule. Proc. Natl Acad. Sci. USA 93, 7178–7183 (1996).

    Article  CAS  Google Scholar 

  18. Vales-Gomez, M., Reyburn, H. T., Mandelboim, M. & Strominger, J. L. Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity 9, 337–344 (1998).

    Article  CAS  Google Scholar 

  19. Maenaka, K. et al. Killer cell immunoglobulin receptors and T cell receptors bind peptide-major histocompatibility complex class I with distinct thermodynamic and kinetic properties. J. Biol. Chem. 274, 28329–28334 (1999).

    Article  CAS  Google Scholar 

  20. Fan, Q. R. et al. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature 389, 96–100 (1997).

    Article  CAS  Google Scholar 

  21. Fan, Q. R. & Wiley, D. C. Structure of human leukocyte antigen (HLA)-Cw4, a ligand for the KIR2D natural killer cell inhibitory receptor. J. Exp. Med. 190, 113–123 (1999).

    Article  CAS  Google Scholar 

  22. Rajagopalan, S. & Long, E. O. The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. J. Exp. Med. 185, 1523–1528 (1997).

    Article  CAS  Google Scholar 

  23. Lawrence, M. C. & Coleman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993).

    Article  CAS  Google Scholar 

  24. Tormo, J., Natarajan, K., Margulles, D. H. & Mariuzza, R. A. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631 (1999).

    Article  CAS  Google Scholar 

  25. Matsumoto, N., Mitsuki, M., Tajima, K., Yokoyama, W. M. & Yamamoto, K. The functional binding site for the C-type lectin-like natural killer cell receptor Ly49A spans three domains of its major histocompatibility complex class I ligand. J. Exp. Med. 193, 147–158 (2001).

    Article  CAS  Google Scholar 

  26. Baker, B. M., Ding, Y. -H., Garboczi, D. N., Biddison, W. E. & Wiley, D. C. Structural, biochemical and biophysical studies of HLA-A2/altered peptide ligands binding to viral-peptide specific human T-cell receptors. Cold Spring Harb. Symp. Quant. Biol. 64, 235–241 (1999).

    Article  CAS  Google Scholar 

  27. Garcia, K. C. et al. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166–1172 (1998).

    Article  CAS  Google Scholar 

  28. Garcia, K. C., Teyton, L. & Wilson, I. A. Structural basis of T cell recognition. Annu. Rev. Immunol. 17, 369–397 (1999).

    Article  CAS  Google Scholar 

  29. Ysern, X., Li, H. & Mariuzza, R. A. Imperfect interfaces. Nature Struct. Biol. 5, 412–414 (1998).

    Article  CAS  Google Scholar 

  30. Reinherz, E. L. et al. The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286, 1913–1921 (1999).

    Article  CAS  Google Scholar 

  31. Clackson, T. & Wells, J. A. A hot spot of binding energy in a hormone-receptor interface. Science 267, 383 (1995).

    Article  CAS  Google Scholar 

  32. Clackson, T., Ultsch, M. H., Wells, J. A. & de Vos, A. M. Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity. J. Mol. Biol. 277, 1111–1128 (1998).

    Article  CAS  Google Scholar 

  33. de Vos, A. M., Ultsch, M. & Kossiakoff, A. A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255, 306–312 (1992).

    Article  CAS  Google Scholar 

  34. Somers, W., Ultsch, M., de Vos, A. M. & Kossiakoff, A. A. The X-ray structure of a growth hormone-prolactin receptor complex. Nature 372, 478–481 (1994).

    Article  CAS  Google Scholar 

  35. Livnah, O. et al. Funtional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 Å. Science 273, 464–471 (1996).

    Article  CAS  Google Scholar 

  36. Snyder, G. A., Brooks, A. G. & Sun, P. D. Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2. Proc. Natl Acad. Sci. USA 96, 3864–3869 (1999).

    Article  CAS  Google Scholar 

  37. Maenaka, K., Juji, T., Stuart, D. I. & Jones, E. Y. Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-Cw3-related MHC class I. Structure 7, 391–398 (1999).

    Article  CAS  Google Scholar 

  38. Davis, D. M. et al. The human natural killer cell immune synapse. Proc. Natl Acad. Sci. USA 96, 15062–16067 (1999).

    Article  CAS  Google Scholar 

  39. Adams, E. J., Thomson, G. & Parham, P. Evidence for an HLA-C-like locus in the orangutan Pongo pygmaeus. Immunogenetics 49, 865–871 (1999).

    Article  CAS  Google Scholar 

  40. Litwin, V., Gumperz, J., Parham, P., Phillips, J. H. & Lanier, L. L. NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J. Exp. Med. 180, 537–543 (1994).

    Article  CAS  Google Scholar 

  41. Gumperz, J. E., Litwin, V., Phillips, J. H., Lanier, L. L. & Parham, P. The Bw4 public epitope of HLA-B molecules confers reactivity with NK cell clones that express NKB1, a putative HLA receptor. J. Exp. Med. 181, 113–114 (1995).

    Article  Google Scholar 

  42. Wagtmann, N., Rajagopalan, S., Winter, C. C., Peruzzi, M. & Long, E. O. Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity 3, 801–809 (1995).

    Article  CAS  Google Scholar 

  43. Sidney, J. et al. Several HLA alleles share overlapping peptide specificities. J. Immunol. 154, 247–259 (1995).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Navaza, J. AMoRe: an automated package for molecular replacement. Acta Crystallogr. A 50, 157–163 (1994).

    Article  Google Scholar 

  46. Brünger, A. T. et al. Crystallography,NMR system: A new softwear suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

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

    Article  Google Scholar 

  48. Collaborative computational project Number 4. The CCP4 Suite: Programs for protein crystallography. Acta Crystallogr. D 50, 760–776 (1994).

  49. Hendrickson, W. A. Transformations to optimize the superposition of similar structures. Acta Crystallogr. A 35, 158–163 (1979).

    Article  Google Scholar 

  50. Stauber, D. J., DiGabriele, A. D. & Hendrickson, W. A. Structural interactions of fibroblast growth factor receptor with its ligand. Proc. Natl Acad. Sci. USA 97, 49–54 (2000).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  52. Nicholls, A., Charp, 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 

  53. Carson, M. Ribbon models of macromolecules. J. Mol. Graph 5, 103–106 (1987).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Tao for help with data collection, D. N. Garboczi for helpful advice, A. Haykov for inclusion body preparation, N. Siniskaya for peptide and DNA synthesis, D. J. Stauber and W. A. Hendrickson for the program TOSS, C. Watzl for the Lig.1 antibody, I. Vakser for molecular modeling studies, P. Sun for the coordinates of KIR2DL2–HLA-Cw3 complex structure and a preprint of the manuscript, R. Mariuzza for discussion of the Ly49A–H-2Dd complex structure before publication, R. Rajalingam for a preprint of the manuscript on Pygmy Chimpanzee KIR, P. Sliz, K. Mahan, B. Harris and R. Crouse for technical assistance and staff at the X25 beamline of NSLS and F-1 beamline at CHESS for help with data collection. Supported by the Howard Hughes Medical Institute, National Institute of Health and the National Science Foundation (Q. R. F.). D. C. W. is supported by HHMI.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Don C. Wiley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fan, Q., Long, E. & Wiley, D. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1–HLA-Cw4 complex. Nat Immunol 2, 452–460 (2001). https://doi.org/10.1038/87766

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/87766

This article is cited by

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