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*
Department of Pathology and Center for Immunology and
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110; and
Howard Hughes Medical Institute, Division of Basic Immunology, National Jewish Center, Denver, CO 80206
To better understand TCR discrimination of multiple ligands, we
have analyzed the crystal structures of two Hb peptide/I-Ek
complexes that differ by only a single amino acid substitution at the
P6 anchor position within the peptide (E73D). Detailed comparison of
multiple independently determined structures at 1.9 Å resolution
reveals that removal of a single buried methylene group can alter a
critical portion of the TCR recognition surface. Significant variance
was observed in the peptide P5-P8 main chain as well as a rotamer
difference at LeuP8, 
10 Å distal from the substitution. No
significant variations were observed in the conformation of the two MHC
class II molecules. The ligand alteration results in two peptide/MHC
complexes that generate bulk T cell responses that are distinct and
essentially nonoverlapping. For the Hb-specific T cell 3.L2,
substitution reduces the potency of the ligand 1000-fold. Soluble 3.L2
TCR binds the two peptide/MHC complexes with similar affinity, although
with faster kinetics. These results highlight the role of subtle
variations in MHC Ag presentation on T cell activation and
signaling.
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