In this step the nucleophilic cysteine attacks the phosphate ester while the aspartic acid protonates the aryl leaving group. This step is followed by hydrolysis of the cysteinyl-phosphate intermediate, using a water molecule that is activated by the same aspartate, now acting as a general base; both steps require the WPD-loop to be closed. Positioning of the nucleophilic water is assisted by a glutamine residue on the Q-loop, another conserved protein element in classical PTPs. Another loop common to the classical PTPs is the E-loop, which contains a conserved glutamate residue that is usually found in a hydrogen bonding interaction with the conserved P-loop arginine, which provides hydrogen bonding interactions for substrate binding and transition state stabilization. the WPD-loop closes toward the P-loop. This brings a conserved aspartic acid into position to protonate the leaving group, followed by a subsequent rate-determining step where the same residue acts as a general base to activate a water molecule in the hydrolysis of the phosphocysteine intermediate. This figure is adapted from ref. . Copyright 2021 American Chemical Society.