PTPs share similar core structural features of a central parallel β-sheet, flanked by α-helices . This core includes a crucial β-loop-α PTP signature motif, the central loop of which, the so-called "P-loop", is critical for phosphate binding and catalysis. Specifically, the Ploop motif (HCX5R) contains a cysteine nucleophile that initiates the catalytic cycle (Figure ), as well as a conserved arginine that positions the substrate and stabilizes the transition state. A second conserved loop, the WPD-loop, undergoes substantial (~10 Å) conformational transitions between catalytically inactive closed and catalytically active open conformations. In doing so, the WPD-loop optimally positions a key aspartic side-chain (D356 in YopH) in the active site where it can act as an acid-base catalyst during the two-step cleavage/hydrolysis mechanism common to all PTPs. Other proximal loops such as the Q-and E-loops are less conformationally mobile but also play important roles in catalysis (Figure , ).