Fig. 4.24 The T-cell receptor binds to the peptide:MHC complex. Panel a: the T-cell receptor binds to the top of a peptide:Mhc class i molecule, touching both the α1 and α2 domain helices. The cDRs of the T-cell receptor are shown in color: the cDR1 and cDR2 loops of the β chain are light and dark blue, respectively; and the cDR1 and cDR2 loops of the α chain are light and dark purple, respectively. The α-chain cDR3 loop is yellow, and the β-chain cDR3 loop is green. The β-chain hV4 loop is in red. The thick yellow line P1–P8 is the bound peptide. Panel b: the outline of the T-cell receptor’s antigen-binding site (thick black line) is superimposed over the top surface of the peptide:Mhc complex (the peptide is shaded dull yellow). The T-cell receptor lies at a somewhat diagonal angle across the peptide:Mhc complex, with the α and β cDR3 loops of the T-cell receptor (3α, 3β, yellow and green, respectively) contacting the center of the peptide. The α-chain cDR1 and cDR2 loops (1α, 2α, light and dark purple, respectively) contact the Mhc helices at the amino terminus of the bound peptide, whereas the β-chain cDR1 and cDR2 loops (1β, 2β, light and dark blue, respectively) make contact with the helices at the carboxy terminus of the bound peptide. courtesy of i.A. Wilson.
central amino acids of the peptide. The T-cell receptor is threaded through a valley between the two high points on the two surrounding α helices that form the walls of the peptide-binding cleft. This can be seen in Fig. 4.25, which shows a view from the end of the peptide-binding groove of a peptide:MHC class II:T-cell receptor complex. Comparison of various peptide: MHC:T-cell receptor complexes shows that the axis of the TCR as it binds the surface of the MHC molecule is rotated somewhat relative to the peptide-binding groove of the MHC molecule (see Fig. 4.24b). In this orientation, the Vα domain makes contact primarily with the amino-terminal half of the bound peptide, whereas the Vβ domain contacts primarily the carboxy-terminal half. Both chains also interact with the α helices of the MHC class I molecule (see Fig. 4.24). The T-cell receptor contacts are not symmetrically distributed over the MHC molecule: whereas the Vα CDR1 and CDR2 loops are in close contact with the helices of the peptide:MHC complex around the amino terminus of the bound peptide, the β-chain CDR1 and CDR2 loops, which interact with the complex at the carboxy terminus of the bound peptide, have variable contributions to the binding.
Comparison of the three-dimensional structure of an unliganded T-cell receptor and the same T-cell receptor complexed to its peptide:MHC ligand shows that the binding results in some degree of conformational change, or ‘induced fit,’ particularly within the Vα CDR3 loop. Subtle variations at amino acids that contact the T-cell receptor can have strikingly different effects on the recognition of an otherwise identical peptide:MHC ligand by the same T cell. The flexibility in the CDR3 loop demonstrated by these two structures helps to explain how the T-cell receptor can adopt conformations that recognize related, but different, peptide ligands.