THE STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE-lB COMPLEXED TO A HIGH AFFINITY INHIBITOR. Andrew D. B. Pannifer^*, Terrence R. Burke Jr.⁺, David Barford^*, ^*Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford, OX1 3QU, UK, ⁺Laboratory of Medicinal Chemistry, Bethesda, MD, USA

The 2.4 Å resolution structure of protein tyrosine phosphatase-lB complexed to the high affinity, non-hydrolyzable inhibitor hydroxy-naphthalene difluorophosphonate is presented. The inhibitor is competitive, binding at the active site with a sub-micromolar K_i and acts as a phosphotyrosine analogue. The labile phosphorus-oxygen bond of phosphotyrosine is replaced by a phosphorus-carbon bond in the inhibitor, thereby rendering the phosphate moiety non-hydrolyzable.

The naphthalene group of the inhibitor mimics the phenyl ring of phosphotyrosine, occupying a hydrophobic cleft formed by tyrosine 46 and phenylalanine 182. The phosphate group occupies the established phosphate binding pocket. Specific interactions between the phenolic oxygen of the inhibitor and residues at the active site of the enzyme have also been identified and these are likely to account for the low K_i.