Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of Grb2-SH2 domain.
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).
Long
Y Q
YQ
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Voigt
J H
JH
Lung
F D
FD
King
C R
CR
Roller
P P
PP
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
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D010456:Peptides, Cyclic; D011506:Proteins