Dual conformations of a T cell receptor Vα homodimer: Implications for variability in VαVβ domain association

The crystal structure of a mutant T cell receptor (TCR) Vα domain containing a grafted third complementarity-determining region (CDR3) from a different Vα was determined at 2.3 Å resolution by molecular replacement using the wild-type Vα structure as a search model. Like the wild-type Vα domain, the mutant crystallized as a homodimer very similar to TCR VαVβ and antibody V(L)V(H) heterodimers, with the CDR loops disposed to form part of the antigen-binding site. However, the relative orientation of the two chains in the mutant Vα homodimer differs from that in the wild-type by a rotation of 14°such that the buried surface area in the dimer interface of the mutant is 140 Ų less than in the wild-type. While the residues forming the interface are essentially the same in the two structures, there are only four pairs of interface hydrogen bonds in the case of the mutant compared with eight for the wild-type. These results suggest that multiple relative orientations of the Vα and Vβ domains of TCRs may be possible, providing a significant contribution to TCR combining site diversity.