Mapping the X+1 binding site of the Grb2-SH2 domain with alpha,alpha-disubstituted cyclic alpha-amino acids

A series of phosphopeptides containing alpha,alpha-disubstituted cyclic alp ha-amino acids (Ac(n)c, 3 less than or equal to n less than or equal to 7; n refers to the number of carbons in the ring) at the X+1 position of Ac-Ty r(PO3H2)-X+1-Asn-NH2 has been synthesised and their inhibitory activity as antagonists of the Grb2-SH2 domain has been determined in competitive bindi ng assays. The SAR data obtained have been interpreted by using models cons tructed from the X-ray structure of the ligand-bound Grb2-SH2 domain. The u sed of alpha,alpha-disubstituted cyclic alpha-amino acids to map the bindin g pockets of proteins expands the classical alanine scan concept and takes advantage of the known conformational preferences of these amino acids. (C) 1999 Elsevier Science Ltd. All rights reserved.