The interaction between the T-cell receptor and an antigen bound to an MHC molecule is central to both humoral and cell-mediated responses. The molecular elements of this interaction have now been described in detail by x-ray crystallography for TCR molecules binding to peptide-MHC class I and class II complexes. A three-dimensional structure has been determined for the trimolecular complex, including TCR a and p chains and an HLA-A2 molecule to which an antigenic peptide is bound. Separate studies describe a mouse TCR molecule bound to peptides com-plexed with the mouse class I molecule H-2Kb and with the mouse class II IAk molecule. The comparisons of the TCR complexed with either class I or class II suggest that there are differences in how the TCR contacts the MHC-peptide complex. Newly added to our library of TCR structures is that of a 78 receptor bound to an antigen that does not require processing.
From x-ray analysis, the TCR-peptide-MHC complex consists of a single TCR molecule bound to a single MHC molecule and its peptide. The TCR contacts the MHC molecule through the TCR variable domains (Figure 9-13 a,b). Although the structures of the constant region of the TCR a chain and the MHC a3 domain were not clearly established by studies of the crystallized human complexes (see Figure 9-13a), the overall area of contact and the structure of the complete TCR variable regions were clear. The constant regions were established by studies of the mouse complex, which showed the orientation proposed for the human models (see Figure 9-13b). Viewing the MHC molecule with its bound peptide from above, we can see that the TCR is situated across it diagonally, relative to the long dimension of the peptide (Figure 9-13c). The CDR3 loops of the TCR a and p chains meet in the center of the peptide; and the CDR1 loop of the TCR a chain is at the N terminus of the peptide, while CDR1 of the p chain is at the C terminus of the peptide. The CDR2 loops are in contact with the MHC molecule; CDR2a is over the a2 domain alpha helix and CDR2p over the a1 domain alpha helix (Figure 9-13c). A space-filling model of the binding site viewed from above (looking down into the MHC cleft) indicates that the pep-tide is buried beneath the TCR and therefore is not seen from this angle (Figure 9-13d). The data also show that the fourth hypervariable regions of the a and p chains are not in contact with the antigenic peptide.
As predicted from data for immunoglobulins, the recognition of the peptide-MHC complex occurs through the variable loops in the TCR structure. CDR1 and CDR3 from both the TCR a and the TCR p chain contact the peptide and a large area of the MHC molecule. The peptide is buried (see Figure 9-13d) more deeply in the MHC molecule than it is in the TCR, and the TCR molecule fits across the MHC molecule, contacting it through a flat surface of the TCR at the "high points" on the MHC molecule. The fact that the CDR1 region contacts both peptide and MHC suggests that regions other than CDR3 are involved in pep-tide binding.
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