CRYSTAL STRUCTURE AT 1.0Å RESOLUTION OF HUMAN p56lck SH2 DOMAIN IN COMPLEX WITH A SHORT PHOSPHOTYROSYL PEPTIDE. L. Tong, T. C. Warren, J. King, R. Betageri, J. Rose and S. Jakes, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P. O. Box 368, Ridgefield, CT 06877, U.S.A

SH2 domains are modules of about 100 amino acid residues and bind to phosphotyrosine-containing motifs in a sequence-specific manner. They play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. The protein tyrosine kinase p56lck is a member of the src family and is involved in T-cell activation. The crystal structure of its SH2 domain with an 11-residue high-affinity peptide [1] showed that the phosphotyrosine (pY) and the Ile residue at the pY+3 position are recognized by the SH2 domain. We have determined the crystal structure of this SH2 domain in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Ile (pYEEI peptide) at 1.0Å resolution [2]. The structural analysis at atomic resolution reveals that residue Arg 134 ([[alpha]][[Alpha]]2), which interacts with the phosphotyrosine side chain, is present in two conformations in the complex. This structure will be compared with those of other complexes.

[1] Eck, M.J., Shoelson, S.E., Harrison, S.C. (1993). Nature, 362, 87.

[2] Tong, L., Warren, T.C., King, J., Betageri, R., Rose, J., Jakes, S. (1996). J. Mol. Biol. 256, 601.