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 alpha-amino acids (Ac(n)c, 3 < or = n < or = 7; n refers to the number of carbons in the ring) at the X(+1) position of Ac-Tyr(PO3H2)-X(+1)-Asn-NH2 has been synthesised and their inhibitory activity as antagonists of the Grb2-SH2 domain has been determined in competitive binding assays. The SAR data obtained have been interpreted by using models constructed from the X-ray structure of the ligand-bound Grb2-SH2 domain. The used of alpha,alpha-disubstituted cyclic alpha-amino acids to map the binding pockets of proteins expands the classical alanine scan concept and takes advantage of the known conformational preferences of these amino acids.
García-Echeverría
C
C
Novartis Pharma Inc., Oncology Research Department, Basel, Switzerland. carlos.garcia-echeverria@pharma.novartis.com
Gay
B
B
Rahuel
J
J
Furet
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P
D048868:Adaptor Proteins, Signal Transducing; D000598:Amino Acids, Cyclic / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D051380:GRB2 Adaptor Protein; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D000598:Amino Acids, Cyclic; D051380:GRB2 Adaptor Protein; D011506:Proteins