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  • Title: Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain.
    Author: Llinaś-Brunet M, Beaulieu PL, Cameron DR, Ferland JM, Gauthier J, Ghiro E, Gillard J, Gorys V, Poirier M, Rancourt J, Wernic D, Betageri R, Cardozo M, Jakes S, Lukas S, Patel U, Proudfoot J, Moss N.
    Journal: J Med Chem; 1999 Feb 25; 42(4):722-9. PubMed ID: 10052978.
    Abstract:
    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 The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine.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.
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