Conformationally constrained peptide analogues of pTyr-Glu-Glu-Ile as inhibitors of the Src SH2 domain binding.
A series of conformationally constrained peptides were designed and synthesized as the Src SH2 domain ligands based on a tetrapeptide sequence pTyr-Glu-Glu-Ile (pYEEI). In general, the constrained peptides such as compounds 6, 7, and 11 (IC(50) = 1.1-1.5 microM) showed higher binding affinities to the Src SH2 domain relative to the corresponding linear peptides 8a, 9a, and 13a, respectively (IC(50) > 100 microM), and pYEEI (IC(50) = 6.5 microM), as evaluated by a fluorescence polarization assay. Molecular modeling studies revealed that in constrained peptides, the isoleucine side chain penetrates very deeply into the hydrophobic binding pocket (P + 3 site) of the Src SH2 domain. These constrained peptides can serve as novel templates for the design of small and nonpeptidic inhibitors of the Src SH2 domain.
Nam
Nguyen-Hai
NH
Department of Biomedical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Ye
Guofeng
G
Sun
Gongqin
G
Parang
Keykavous
K
D001665:Binding Sites; D001667:Binding, Competitive; D005454:Fluorescence Polarization; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D009842:Oligopeptides; D010748:Phosphopeptides; C487410:phosphotyrosyl-glutamyl-glutamyl-isoleucine; D016392:Proto-Oncogene Proteins pp60(c-src)