CRYSTAL-STRUCTURE OF YERSINIA PROTEIN-TYROSINE-PHOSPHATASE AT 2.5-ANGSTROM AND THE COMPLEX WITH TUNGSTATE

PROTEIN tyrosine phosphatases (PTPases) and kinases coregulate the cri tical levels of phosphorylation necessary for intracellular signalling , cell growth and differentiation(1,2). Yersinia, the causative bacter ia of the bubonic plague and other enteric diseases, secrete an active PTPase(3), Yop51, that enters and suppresses host immune cells(4,5). Though the catalytic domain is only similar to 20% identical to human PTP1B(6), the Yersinia PTPase contains all of the invariant residues p resent in eukaryotic PTPases(7), including the nucleophilic Cys 403 wh ich forms a phosphocysteine intermediate during catalysis(3,8-10). We present here structures of the unliganded (2.5 Angstrom resolution) an d tungstate-bound (2.6 Angstrom) crystal forms which reveal that Cys 4 03 is positioned at the centre of a distinctive phosphate-binding loop . This loop is at the hub of several hydrogen-bond arrays that not onl y stabilize a bound oxyanion, but may activate Cys 403 as a reactive t hiolate. Binding of tungstate triggers a conformational change that tr aps the oxyanion and swings Asp 356, an important catalytic residue(7) , by similar to 6 Angstrom into the active site. The same anion-bindin g loop in PTPases is also found in the enzyme rhodanese(11).