Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of Grb2-SH2 domain

Y Q Long; J H Voigt; F D Lung; C R King; P P Roller

doi:10.1016/s0960-894x(99)00379-0

Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of Grb2-SH2 domain

Bioorg Med Chem Lett. 1999 Aug 2;9(15):2267-72. doi: 10.1016/s0960-894x(99)00379-0.

Authors

Y Q Long¹, J H Voigt, F D Lung, C R King, P P Roller

Affiliation

¹ Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

PMID: 10465559
DOI: 10.1016/s0960-894x(99)00379-0

Abstract

Systematic modification of amino acid at position Y-2 of a library-derived non-phosporylated thioether-cyclized peptide, cyclo(CH2CO-Glu2-Leu-Tyr0-Glu-Asn-Val-Gly-Met-Tyr-Cys) -amide, aided by molecular modeling, demonstrates that the Glu(-2) sidechain compensates for the absence of Tyr0 phosphorylation in retaining effective binding to Grb2-SH2 domain. Replacement of Glu(-2) with gamma-carboxyglutamic acid produced a high affinity inhibitor, the first example with submicromolar affinity (IC50 = 640 nM).

MeSH terms

Adaptor Proteins, Signal Transducing*
Amino Acid Sequence
Binding, Competitive
GRB2 Adaptor Protein
Models, Molecular
Molecular Sequence Data
Peptides, Cyclic / chemical synthesis*
Peptides, Cyclic / pharmacology
Protein Conformation
Proteins / antagonists & inhibitors
Proteins / chemistry
Proteins / drug effects
Proteins / metabolism*
Structure-Activity Relationship
Surface Plasmon Resonance
src Homology Domains*

Substances

Adaptor Proteins, Signal Transducing
GRB2 Adaptor Protein
Peptides, Cyclic
Proteins