Structure-based design of peptidomimetic antagonists of p56lck SH2 Domain

Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56lck SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.