Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics

Protein tyrosine phosphatases regulate diverse cellular processes and repre sent important targets for therapeutic intervention in a number of diseases , The crystal structures of protein tyrosine phosphatase 1B (PTP1B) in comp lex with small molecule inhibitors based upon two classes of phosphotyrosin e mimetics, the (difluoronaphthylmethyl)phosphonic acids and the fluoromalo nyl tyrosines, have been determined to resolutions greater than 2.3 Angstro m. The fluoromalonyl tyrosine residue was incorporated within a cyclic hexa peptide modeled on an autophosphorylation site of the epidermal growth fact or receptor. The structure of this inhibitor bound to PTP1B represents the first crystal structure of a non-phosphonate-containing inhibitor and revea ls the mechanism of phosphotyrosine mimicry by the fluoromalonyl tyrosine r esidue and the nature of its interactions within the catalytic site of PTP1 B, In contrast to complexes of PTP1B with phosphotyrosine-containing peptid es, binding of the fluoromalonyl tyrosine residue to the catalytic site of PTP1B is not accompanied by closure of the catalytic site WPD loop. Structu res of PTP1B in complex with the (difluoronaphthylmethyl)phosphonic acid de rivatives reveal that substitutions of the naphthalene ring modulate the mo de of inhibitor binding to the catalytic site and provide the potential for enhanced inhibitor affinity and the generation of PTP-specific inhibitors. These results provide a framework for the rational design of higher affini ty and more specific phosphotyrosine mimetic inhibitors of not only protein tyrosine phosphatases but also SH2 and PTB domains.