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CDR3 loop flexibility contributes to the degeneracy of TCR recognition

Nature Immunology volume 4, pages 241–247 (2003)Cite this article

Abstract

T cell receptor (TCR) binding degeneracy lies at the heart of several physiological and pathological phenomena, yet its structural basis is poorly understood. We determined the crystal structure of a complex involving the BM3.3 TCR and an octapeptide (VSV8) bound to the H-2Kb major histocompatibility complex molecule at a 2.7 Å resolution, and compared it with the BM3.3 TCR bound to the H-2Kb molecule loaded with a peptide that has no primary sequence identity with VSV8. Comparison of these structures showed that the BM3.3 TCR complementarity-determining region (CDR) 3α could undergo rearrangements to adapt to structurally different peptide residues. Therefore, CDR3 loop flexibility helps explain TCR binding cross-reactivity.

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Figure 1: Affinity of BM3.3 TCR binding to the VSV8-H-2Kb ligand.
Figure 2: Relative orientation of the BM3.3 CDRs when docked on the VSV8-H-2Kb or on the pBM1-H-2Kb ligand.
Figure 3: Superimposition of the pBM1 and VSV8 peptides in the H-2Kb groove.
Figure 4: Views of pBM1 and VSV8 peptide read-out by the BM3.3 TCR.
Figure 5: Footprint of BM3.3 TCR on the pBM1-H-2Kb and VSV8-H-2Kb surfaces.

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Acknowledgements

We thank A. Guimezanes, A.-M. Schmitt-Verhulst, C. Kellenberger, L. Leserman and P. Golstein for discussions and comments on the manuscript, and C. Rieckel (beamline ID13), J.L. Ferrer (beamline FIP-BM30A), S. Arzt (beamline ID14-eh1), W. Burmeister (beamline ID14-eh3) and J. Lescar (beamline ID14-eh4) for help with synchrotron data collections at the ESRF (Grenoble). This work was supported by institutional grants from CNRS, CEA and INSERM, and specific grants from ARC, CNRS (programme PCV) and the European Communities (project EPI-PEP-VAC QLK2-CT-2002-00620). P.A.v.d.M. and A.K. are supported by the UK Medical Research Council.

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Authors and Affiliations

  1. Laboratoire de Cristallographie et Cristallogenèse des Protéines, Institut de Biologie Structurale J.-P. Ebel, CEA-CNRS-UJF, 41 rue Jules Horowitz, Grenoble, F-38027 Cedex 1, France

    Jean-Baptiste Reiser, Claudine Darnault, Juan Carlos Fontecilla-Camps & Dominique Housset

  2. Centre d'Immunologie de Marseille-Luminy INSERM-CNRS-Université de la Méditerranée, Parc Scientifique de Luminy, Case 906, Marseille, F-13288 Cedex 9, France

    Claude Grégoire, Thomas Mosser, Gilbert Mazza & Bernard Malissen

  3. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK

    Alice Kearney & P. Anton van der Merwe

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Reiser, JB., Darnault, C., Grégoire, C. et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat Immunol 4, 241–247 (2003). https://doi.org/10.1038/ni891

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