conformational determinants of phosphotyrosine peptides complexed with the src sh2 domainphosphotyrosine肽构象因素包裹着src sh2域.pdfVIP

Conformational Determinants of Phosphotyrosine Peptides Complexed with the Src SH2 Domain 1 2 2 2 ´ ` 1,3 1,4,5 Joseph Nachman *, Gerry Gish , Cristina Virag , Tony Pawson , Regis Pomes , Emil Pai 1 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada, 2 Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, 3 Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada, 4 Departments of Medical Biophysics and Molecular Biology, University of Toronto, Toronto, Ontario, Canada, 5 Division of Genomics and Proteomics, Ontario Cancer Institute, Toronto, Ontario, Canada Abstract The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the ‘‘two-pronged plug two-hole socket’’ model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these pept