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Cyclic peptides incorporating 4-carboxyphenylalanine and phosphotyrosine are potent inhibitors of pp60(c-)(src).

Abstract：

:The protein tyrosine kinase, pp60(c-)(src), is involved in cellular signaling and is activated during mitosis and in various tumors. We have been employing cyclic decapeptides to identify the determinants for substrate binding and phosphorylation to develop inhibitors competitive with protein substrates of Src. A structure-activity study [McMurray, J. S., Budde, R. J. A., Ke, S., Obeyesekere, O. U., Wang, W., Ramdas, L., and Lewis, C. A. (1998) Arch. Biochem. Biophys. 355, 124] revealed that, at the position 3 residues C-terminal to the phosphorylated tyrosine (Y + 3), both glutamic acid and phenylalanine gave identical K(i), K(m), and V(max) values. We hypothesized that the area of Src that binds the Y + 3 residue contains either a positively charged lysine or an arginine, capable of ionic interactions with glutamic acid or cation-pi interactions with phenylalanine. To test this hypothesis, a series of phenylalanine analogues were substituted at position 7 (the Y + 3 residue) in cyclo(Asp(1)-Asn(2)-Glu(3)-Tyr(4)-Ala(5)-Phe(6)-Phe(7)-Gln(8)-D-Phe(9 )-Pro(10)). Of these, 4-carboxyphenylalanine (4-Cpa) and phosphotyrosine resulted in high affinity peptides exhibiting K(i) values of 0.85 and 1.1 microM, respectively, 180- and 130-fold increases in potency over the parent cyclic peptide (K(i) = 150 microM). These peptides were noncompetitive with respect to ATP and competitive against the phosphate-accepting substrate, polyGlu(4)Tyr. The truncated cyclic peptide, cyclo(Phe-4-Cpa-Gln-D-Phe-Pro-Asp-Aca) (Aca = epsilon-aminocaproic acid), which did not contain tyrosine, was also a competitive inhibitor with a K(i) value of 24 microM. We conclude that these cyclic peptides bind to a positively charged area that is near the phosphate transfer region of the active site of Src but does not necessarily include the tyrosine-binding pocket. Furthermore, the 4-Cpa-containing cyclic decapeptide shows remarkable selectivity in the inhibition of Src versus the src family members Yes and Lck, as well as other protein tyrosine kinases, Ser/Thr kinases, and other ATP-utilizing enzymes.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Wang W,Ramdas L,Sun G,Ke S,Obeyesekere NU,Budde RJ,McMurray JS

doi

10.1021/bi992994f

subject

Has Abstract

pub_date

2000-05-02 00:00:00

pages

5221-8

issue

eissn

0006-2960

issn

1520-4995

pii

bi992994f

journal_volume

pub_type

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Cyclic peptides incorporating 4-carboxyphenylalanine and phosphotyrosine are potent inhibitors of pp60(c-)(src).