Solution structure of the SH2 domain of Grb2 complexed with the Shc-derived phosphotyrosine-containing peptide

The solution structure of growth factor receptor-bound protein 2 (Grb2) SH2 complexed with a Shc-derived phosphotyrosine (pTyr)-containing peptide was determined by nuclear magnetic resonance (NMR) spectroscopy. The pTyr bind ing site of Grb2 SH2 was similar to those of other SH2 domains. Ln contrast , the amino acid residues C-terminal to pTyr did not form an extended struc ture because of steric hindrance caused by a bulky side-chain of Trp121 (EF 1). As a result, the peptide formed a turn-structure on the surface of Grb2 SH2. The asparagine residue at the pTyr + 2 position of the She-peptide in teracted with the main-chain carbonyl groups of Lys109 and Leu120. The pres ent solution structure was similar to the crystal structure reported for Gr b2 SH2 complexed with a BCR-Abl-derived phosphotyrosine-containing peptide. Finally, the structure of Grb2 SH2 domain was compared with those of the c omplexes of Src and phospholipase C-gamma 1 with their cognate peptides, sh owing that the specific conformation of the peptide was required for bindin g to the SH2 domains. (C) 1999 Academic Press.