The molecular mechanism through which the interaction of a clonotypic TCR with peptide/MHC (p/MHC) complexes leads to T cell activation is not yet fully understood. We have studied a high affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-Dd) by combining crystallographic, NMR, and functional data. In addition to conformational changes in complementarity determining regions (CDR) of the TCR, seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR chain dynamics reveals significant chemical shift effects in sites removed from the MHC binding site. In particular, a remodeling of electrostatic interactions near the C H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests an allosteric mechanism for TCR signaling. The contribution of these TCR residues to signal transduction is supported by our mutagenesis results and by T cell functional assays.
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