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Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses

Nature volume 410, pages 608–611 (2001)Cite this article

An Erratum to this article was published on 31 May 2001

Abstract

Optimal immune responses require both an antigen-specific and a co-stimulatory signal. The shared ligands B7-1 and B7-2 on antigen-presenting cells deliver the co-stimulatory signal through CD28 and CTLA-4 on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it. Numerous animal studies1,2 and recent clinical trials3,4 indicate that manipulating these interactions holds considerable promise for immunotherapy. With the consequences of these signals well established, and details of the downstream signalling events emerging5,6,7, understanding the molecular nature of these extracellular interactions becomes crucial. Here we report the crystal structure of the human CTLA-4/B7-1 co-stimulatory complex at 3.0 Å resolution. In contrast to other interacting cell-surface molecules, the relatively small CTLA-4/B7-1 binding interface exhibits an unusually high degree of shape complementarity. CTLA-4 forms homodimers through a newly defined interface of highly conserved residues. In the crystal lattice, CTLA-4 and B7-1 pack in a strikingly periodic arrangement in which bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers. This zipper-like oligomerization provides the structural basis for forming unusually stable signalling complexes at the T-cell surface, underscoring the importance of potent inhibitory signalling in human immune responses.

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Figure 1: Structural comparison of sCTLA-4/sB7-1 complex with uncomplexed forms of sCTLA-4 and sB7-1.
Figure 2: Overview of receptor–ligand interactions.
Figure 4: A 3 Å resolution electron-density map in the region of the receptor–ligand binding site.
Figure 3: Molecular association of sCTLA-4 and sB7-1 in the crystal lattice.

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Acknowledgements

We thank R. Zollner and his colleagues for large scale cell culture, and D. I. Stuart and E. Y. Jones for helpful comments. We also thank the staff at Advanced Light Source for assistance with data collection. S.I. and S.J.D. are supported by the Wellcome Trust and the Human Frontier Science Programme.

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Author notes

  1. Yan Zhang

    Present address: Pfizer Cambridge Discovery Technology Center, 620 Memorial Drive, Cambridge, Massachusetts, 02139, USA

Authors and Affiliations

  1. Departments of Biological Chemistry and Musculoskeletal Sciences, Wyeth Research, 87 Cambridge Park Drive, Cambridge, 02140, Massachusetts, USA

    Carin C. Stamper, Yan Zhang, James F. Tobin, David V. Erbe, Mark L. Stahl, Jasbir Seehra, William S. Somers & Lidia Mosyak

  2. Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Shinji Ikemizu

  3. Nuffield Department of Clinical Medicine, The University of Oxford, John Radcliffe Hospital, Headington, OX3 9DU, Oxford, UK

    Simon J. Davis

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Correspondence to William S. Somers.

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Stamper, C., Zhang, Y., Tobin, J. et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 410, 608–611 (2001). https://doi.org/10.1038/35069118

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