As noted above, differences in overall covalent inhibition across the tested phosphatases showed an approximately inverse correlation with the catalytic activity of those phosphatases. Thus, we hypothesize that divergent structural features which affect catalytic activity may also affect covalent inhibition. The WPD loop of phosphatases is the active site feature that has been most directly connected to differences in catalytic activity between phosphatases. Sequence divergence in this region can lead to differences loop dynamics, which in turn impacts catalysis. Two proline residues found in PTP1B (Pro 185 and Pro 188), but not YopH, are reported to constrain the dynamics of the PTP1B WPD loop, potentially leading to its lower enzyme activity. While Pro 185 is invariant in the human PTPs, Pro 188 is replaced by threonine in CD148, and alanine in HePTP, the least and most inhibitable human phosphatases examined in our study, respectively (Figure ). Previous studies have shown that the P188A mutation in PTP1B alters WPD loop structure and dynamics and also impacts the rates of multiple steps in the phosphatase catalytic cycle. Based on these observations, we expect that the identity of the P188-analogous residue in other phosphatases is likely to also impact their rates of covalent inhibition.