Cyclic peptides as probes of the substrate binding site of the cytosolic tyrosine kinase, pp60c-src

Archives of Biochemistry and Biophysics
J S McMurrayC A Lewis

Abstract

A series of 48 cyclic peptides based on the amino acid sequence surrounding the autophosphorylation site of pp60(c-src) was synthesized and each was tested as both a substrate and an inhibitor of this protein tyrosine kinase. Starting with cyclo(Asp1-Asn2-Gln3-Tyr4-Ala5-Ala6-Arg7-Gln8-d- Phe9-Pro10) a six-amino-acid survey was performed at positions 1 through 8 to determine which positions were critical for affinity and phosphorylation and which amino acids produced the greatest activity. Our survey found that Arg7 was detrimental for binding and phosphorylation and that aromatic residues were preferred at this position. Further increases in affinity were obtained with hydrophobic residues at position 6 with the optimum for both affinity and phosphorylation being Phe. Changes on the "amino-terminal" side of Tyr4 resulted in reduced Vmax values, illustrating the requirement for acidic residues in peptidic tyrosine kinase substrates. The result of the survey was cyclo(Asp1-Asn2-Gln3-Tyr4-Ala5-Phe6-Phe7-Gln8-d-Phe 9-Pro10). The change of residues 6 and 7 resulted in a 42-fold increase in affinity and no increase in Vmax. As a substrate, this peptide displayed Michaelis-Menten kinetics at saturating ATP conditions. As an inhibitor,...Continue Reading

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Citations

Jul 29, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·L RamdasR J Budde
Sep 6, 2006·Experimental Cell Research·Gang ZengSatdarshan P S Monga
Oct 19, 1999·Rapid Communications in Mass Spectrometry : RCM·B SchillingK F Medzihradszky
Dec 14, 1999·The Journal of Biological Chemistry·S RouraM Duñach
Jan 7, 2005·Journal of Peptide Science : an Official Publication of the European Peptide Society·Diana ImhofSiegmund Reissmann

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