STRUCTURE-BASED DESIGN OF A NOVEL SERIES OF NONPEPTIDE LIGANDS THAT BIND TO THE PP60(SRC) SH2 DOMAIN

The SH2 domain of pp60(c-src) (Src), a nonreceptor tyrosine kinase, fa cilitates signal transduction in a number of cell types through bindin g to cognate phosphorylated protein sequences. Phosphotyrosine-contain ing peptides have been shown to bind to the Src SH2 domain with microm olar affinity. Guided by the X-ray crystal structure of a phosphorylat ed peptide bound to the Src SH2 domain, we have designed a de novo ser ies of small molecule ligands that bind with affinity comparable to th e parent phosphopeptide. An X-ray crystal structure of the Src SH2 dom ain bound with a nonpeptide analog from this series verifies interacti ons targeted in the molecular design. However, a unique mode of bindin g has been revealed for the P-site phenyl phosphate group of the nonpe ptide that differs from that observed for the phosphotyrosine side cha in in peptide ligands bound to the Src SH2 domain. This novel binding mode is being used in guiding future design efforts.