Dynamic Analysis of Phosphatase 1B WPD Loop

Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as 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 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 between the open and closed states and as well as the effect of this motion on the PTP1B conformational activation mechanism. Our results indicate that WPD loop motion is governed by hydrophobic interactions between the WPD loop, loop 11 and α3 and α6 helices. The simulations are repeated in the presence and absence of the α7 helix. The hydrophobic interaction network is better maintained in the presence of the α7 helix, suggesting that the high mobility of α7 helix allows the transition between the open and closed states of the WPD loop. In addition, the formation of a hydrogen bond between the backbone oxygen of Trp-179 and the sidechain nitrogens of 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.