Point mutations on noncatalytic WPD-loop residues in PTPs rarely affect the secondary structures of the active sites, however, differences in the WPD-loop dynamics are likely to be observed. 9, 14 A previous study of point variants of corresponding residues on the WPD-loops of PTP1B and YopH demonstrated that a single mutation changes the pH-dependency of catalysis, loop dynamics, and loop equilibrium. Residues S418, H422, and E427 are located on the Nterminal, central portion, and C-terminal of the WPD-loop in SHP-1. Although SHP-1 has a modest difference in the backbone positioning of its WPD-loop compared to YopH and PTP1B (Figure ), residues S418, H422, and E427 are likely to experience, as well as affect, significant conformational dynamics between loop closed and open forms. In PTP1B, the central portion of the WPD-loop and residues E186 and S187 exhibits relatively high mobility compared to the rest of the loop. Due to the high sequence identity and structural similarity of the WPD-loop of SHP-1 and PTP1B, it would not be unreasonable to assume that SHP-1 exhibits similar dynamics and flexibility of the loop to PTP1B, and that these SHP-1 mutations might alter pH dependency by changing loop conformational equilibria. 9 (SHP-1 PDB ID: 4GRY, 31 PTP1B PDB ID: 3I80, YopH PDB ID: 2I42 57 ).