Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain.
Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56lck (Lck) with an affinity of 0.1 microM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.
Boehringer Ingelheim Pharmaceuticals Inc., 175 Briar Ridge Road, Ridgefield, Connecticut 06877, USA.
M
M
Llinaś-Brunet
P L
PL
Beaulieu
D R
DR
Cameron
J M
JM
Ferland
J
J
Gauthier
E
E
Ghiro
J
J
Gillard
V
V
Gorys
M
M
Poirier
J
J
Rancourt
D
D
Wernic
R
R
Betageri
M
M
Cardozo
S
S
Jakes
S
S
Lukas
U
U
Patel
J
J
Proudfoot
N
N
Moss
D001667:Binding, Competitive; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008958:Models, Molecular; D019000:Phosphotyrosine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; D019000:Phosphotyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)