Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain.
The observation that anthranilic acid as N-terminal group produces a dramatic increase of the binding affinity of the phosphopeptide sequence Glu-pTyr-Ile-Asn for the Grb2-SH2 domain was rationalized by molecular modeling. The model, which invokes a stacking interaction between the N-terminal group and the SH2 domain residue Arg alpha A2, was subsequently used to design the 3-aminobenzyloxycarbonyl N-terminal group. The latter confers high affinity (IC50 = 65 nM in an ELISA assay) to the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain.
Furet
P
P
Novartis Pharma Inc., Oncology Research Department, Basel, Switzerland. furet@chbs.ciba.com
Gay
B
B
García-Echeverría
C
C
Rahuel
J
J
Fretz
H
H
Schoepfer
J
J
Caravatti
G
G
D048868:Adaptor Proteins, Signal Transducing; D000814:Aniline Compounds / Q000737:chemistry*; D001665:Binding Sites; D051380:GRB2 Adaptor Protein; D008958:Models, Molecular; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D000814:Aniline Compounds; D051380:GRB2 Adaptor Protein; D010748:Phosphopeptides; D011506:Proteins; D011994:Recombinant Proteins