Summary

Src homology 3 (SH3) domains, which are found in many proteins involved in intracellular signal trans-duction, mediate specific protein-protein interac-tions. The three-dimensional structure of the SH3 do-main in the ~85 subunit of the phosphatidylinositol 3-kinase (Pl3K) has been determined by multidimen-sional NMR methods. The molecule consists of four short helices, two 5 turns, and two antiparallel 5 sheets. The 5 sheets are highly similar to correspond-ing regions in the SH3 domain of the tyrosine kinase Src, even though the sequence identity of the two do-mains is low. There is a unique 15 amino acid insert in Pl3K that contains three short helices. There are substantial differences in the identity of the amino acids that make up the receptor site of SH3 domains. The results suggest that while the overall structures of the binding sites in the Pl3K and Src SH3 domains are similar, their ligand binding properties may differ