Analysis of phosphatase 1B WPD loop closure

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin and leptin signaling, and is therefore a major molecular target for the treatment of type II diabetes and obesity. WPD loop is a key element in the mechanism of PTP1B catalysis. In the apo form, WPD loop is usually in an “open” conformation, whereas it closes over the active site upon substrate binding. Here, targeted molecular dynamics (TMD) simulations are reported to examine the transition of the WPD loop from the open to closed states as well as the effect of this motion on the PTP1B conformational activation mechanism. Our results indicate that WPD loop motion is described by some residue-residue interactions between the WPD loop and the active site and the changes of some WPD loop dihedral angles. Trp179 side chain dihedral angle changes gradually during the simulation, while Asp181 backbone dihedral angle makes a jump to the end of the simulation. The formation of hydrogen bonds between Trp-179 and Asp-181 with Arg-221 is observed to mediate the closure of WPD loop. Elucidating the detailed mechanism of PTP1B conformational activation will guide future drug design efforts toward type II diabetes and obesity.