CRYSTAL-STRUCTURES OF THE HUMAN P56(LCK) SH2 DOMAIN IN COMPLEX WITH 2SHORT PHOSPHOTYROSYL PEPTIDES AT 1.0 ANGSTROM AND 1.8 ANGSTROM RESOLUTION

src homology 2 (SH2) domains are modules of about 100 amino acid resid ues and bind to phosphotyrosine-containing motifs in a sequence-specif ic manner. They play important roles in intracellular signal transduct ion and represent potential targets for pharmacological. intervention. The protein tyrosine kinase p56(lck) is a member of the src family an d is involved in T-cell activation. The crystal structure of its SH2 d omain with an Ii-residue peptide showed that the phosphotyrosine and t he lie residue at the pY + 3 position are recognized by the SH2 domain . We present here the crystal structure of the SH2 domain of human p56 (lck) in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu -Ile (pYEEI peptide) at 1.0 Angstrom resolution. The structural analys is at atomic resolution reveals that residue Arg134 (alpha A2), which interacts with the phosphotyrosine side-chain, is present in two confo rmations in the complex. The structure at 1.8 Angstrom resolution of t he complex with the phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Gly (pYEEG peptide), which is Ii-fold less potent, shows another binding mode for the pY + 3 residue as well as rearrangements of the side-chain of Arg 196 (EF3) and one of the water molecules at the base of the pY + 3 poc ket. The structure of the complex with the short pYEEI peptide at atom ic resolution represents a good starting point for the design and opti mization of new inhibitors. Comparative structural analysis of many di fferent inhibitor complexes will be an important component of this dru g discovery process. (C) 1996 Academic Press Limited