BINDING OF A HIGH-AFFINITY PHOSPHOTYROSYL PEPTIDE TO THE SRC SH2 DOMAIN - CRYSTAL-STRUCTURES OF THE COMPLEXED AND PEPTIDE-FREE FORMS

The crystal structure of the Src SH2 domain complexed with a high affinity 11-residue phosphopeptide has been determined at 2.7 angstrom resolution by X-ray diffraction. The peptide binds in an extended conformation and makes primary interactions with the SH2 domain at six central residues: PQ(pY)EEI. The phosphotyrosine and the isoleucine are tightly bound by two well-defined pockets on the protein surface, resulting in a complex that resembles a two-pronged plug engaging a two-holed socket. The glutamate residues are in solvent-exposed environments in the vicinity of basic side chains of the SH2 domain, and the two N-terminal residues cap the phosphotyrosine-binding site. The crystal structure of Src SH2 in the absence of peptide has been determined at 2.5 angstrom resolution, and comparison with the structure of the high affinity complex reveals only localized and relatively small changes.