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 αA2, was subsequently used to design the 3-aminobenzyloxycarbonyl N-terminal group. The latter confers high affinity (IC<INF>50</INF> = 65 nM in an ELISA assay) to the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain.