title: TCR binding to peptide-MHC stabilizes a flexible recognition interface.
abstract: The binding of TCRs to their peptide-MHC ligands is characterized by a low affinity, slow kinetics, and a high degree of cross-reactivity. Here, we report the results of a kinetic and thermodynamic analysis of two TCRs binding to their peptide-MHC ligands, which reveal two striking features. First, significant activation energy barriers must be overcome during both association and dissociation, suggesting that conformational adjustments are required. Second, the low affinity of binding is a consequence of highly unfavorable entropic effects, indicative of a substantial reduction in disorder upon binding. This is evidence that the TCR and/or peptide-MHC have flexible binding surfaces that are stabilized upon binding. Such conformational flexibility, which may also be a feature of primary antibodies, is likely to contribute to cross-reactivity in antigen recognition.
authors: Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors: B E
authors: BE
authors: Willcox
authors: G F
authors: GF
authors: Gao
authors: J R
authors: JR
authors: Wyer
authors: J E
authors: JE
authors: Ladbury
authors: J I
authors: JI
authors: Bell
authors: B K
authors: BK
authors: Jakobsen
authors: P A
authors: PA
authors: van der Merwe
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000276:immunology; D019277:Entropy; D019143:Evolution, Molecular; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011946:Receptors, Antigen / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D013696:Temperature; D014764:Viral Proteins
chemical_list: D015789:HLA-A2 Antigen; D009842:Oligopeptides; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins