Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of GRB2-SH2 domain

Authors
Long, YQ Voigt, JH Lung, FDT King, CR Roller, PP
Citation
Yq. Long et al., Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of GRB2-SH2 domain, BIOORG MED, 9(15), 1999, pp. 2267-2272
Citations number
15
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
9
Issue
15
Year of publication
1999
Pages
2267 - 2272
Database
ISI
SICI code
0960-894X(19990802)9:15<2267:SCROPY>2.0.ZU;2-C
Abstract
Systematic modification of amino acid at position Y-2 of a library-derived non-phosporylated thioether-cyclized peptide, cyclo(CH2CO-Glu(-2)-Leu-Tyr(0 )-Glu-Asn-Val-Gly-Met-Tyr-Cys)-amide, aided by molecular modeling, demonstr ates that the Glu(-2) sidechain compensates for the absence of Tyr phosphor ylation in retaining effective binding to Grb2-SH2 domain. Replacement of G lu(-2) with gamma-carboxyglutamic acid produced a high affinity inhibitor, the first example with submicromolar affinity (IC50 = 640 nM). (C) 1999 Els evier Science Ltd. All rights reserved.