The structure and stability of an HLA-A*0201/octameric tax peptide complexwith an empty conserved peptide-N-terminal binding site

The crystal structure of the human class I MHC molecule HLA-A2 complexed wi th of an octameric peptide, Tax8 (LFGYPVYV), from human T cell lymphotrophi c virus-1 (HTLV-1) has been determined. This structure is compared with a n ewly refined, higher resolution (1.8 Angstrom) structure of HLA-A2 complexe d with the nonameric Tax9 peptide (LLFGYPVYV) with one more N-terminal resi due, Despite the absence of a peptide residue (P1) bound in the conserved N -terminal peptide-binding pocket of the Tax8/HLA-A2 complex, the structures of the two complexes are essentially identical. Water molecules in the Tax 8 complex replace the terminal amino group of the Tax9 peptide and mediate a network of hydrogen bonds among the secondary structural elements at that end of the peptide-binding groove. Thermal denaturation measurements indic ate that the Tax8 complex is much less stable, Delta T-m = 16 degrees C, th an the Tax9 complex, but both can sensitize target cells for lysis by some Tax-specific CTL from HTLV-1 infected individuals. The absence of a Pi pept ide residue is thus not enough to prevent formation of a "closed conformati on" of the peptide-binding site, TCR affinity measurements and cytotoxic T cell assays indicate that the Tax8/HLA-A2 complex does not functionally cro ss-react with the A6-TCR-bearing T cell clone specific for Tax9/HLA-A2 comp lexes.