title: Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of Grb2-SH2 domain.
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).
authors.affiliation: Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Long
authors.forename: J H
authors.initials: JH
authors.lastname: Voigt
authors.forename: F D
authors.initials: FD
authors.lastname: Lung
authors.forename: C R
authors.initials: CR
authors.lastname: King
authors.forename: P P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D051380:GRB2 Adaptor Protein; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D010456:Peptides, Cyclic; D011506:Proteins