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Binding degeneracy is thought to constitute a fundamental property of the T-cell antigen receptor (TCR), yet its structural basis is poorly understood. We determined the crystal structure of a complex involving the BM3.3 TCR and a peptide (pBM8) bound to the H-2K(bm8) major histocompatibility complex (MHC) molecule, and compared it with the structures of the BM3.3 TCR bound to H-2K(b) molecules loaded with two peptides that had a minimal level of primary sequence identity with pBM8. Our findings provide a refined structural view of the basis of BM3.3 TCR cross-reactivity and a structural explanation for the long-standing paradox that a TCR antigen-binding site can be both specific and degenerate. We also measured the thermodynamic features and biological penalties that incurred during cross-recognition. Our data illustrate the difficulty for a given TCR in adapting to distinct peptide-MHC surfaces while still maintaining affinities that result in functional in vivo responses. Therefore, when induction of protective effector T cells is used as the ultimate criteria for adaptive immunity, TCRs are probably much less degenerate than initially assumed.

Original publication

DOI

10.1038/sj.emboj.7601605

Type

Journal article

Journal

EMBO J

Publication Date

04/04/2007

Volume

26

Pages

1972 - 1983

Keywords

Amino Acid Sequence, Animals, Antigens, Complementarity Determining Regions, Crystallography, X-Ray, H-2 Antigens, Ligands, Mice, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Peptides, Protein Structure, Secondary, Receptors, Antigen, T-Cell, Thermodynamics, Tyrosine