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Potent inhibition of insulin receptor dephosphorylation by a hexamer peptide containing the phosphotyrosyl mimetic F2Pmp.

Authors
Type
Published Article
Journal
Biochemical and Biophysical Research Communications
0006-291X
Publisher
Elsevier
Publication Date
Volume
204
Issue
1
Pages
129–134
Identifiers
PMID: 7524496
Source
Medline

Abstract

Phosphonomethyl phenylalanine (Pmp) is a non-hydrolyzable phosphotyrosyl (pTyr) mimetic, which has been incorporated into eleven-mer Pmp-containing peptides that have previously been reported to competitively inhibit the protein-tyrosine phosphatases PTP1 and PTP 1B. We have recently shown that phosphonodifluoromethyl phenylalanine (F2Pmp) is superior to Pmp as a pTyr mimetic in SH2 domain-binding peptides. Herein we find using the hexameric peptide sequence Ac-D-A-D-E-X-L-amide, where X = (D/L)-Pmp or L-F2Pmp, that the half maximal inhibition values of these two peptides against PTP 1B-mediated dephosphorylation of autophosphorylated insulin receptor to be 200 microM and 100 nM, respectively. These data indicate that F2Pmp induces a three orders of magnitude enhancement in affinity relative to Pmp, resulting in an exceptionally potent peptide-based PTP inhibitor. We conclude that F2Pmp may be a generally useful tool in the preparation of selective, high affinity PTP inhibitors.

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