The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.

Shaoyong Lu,Freddie Salsbury,,Lv Geng,Jingmiao Zhang,Qiancheng Shen,Shuai Li,Wenkang Huang,Jian Zhang

doi:10.1371/journal.pone.0097668

Abstract

As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors.

Highlights

Protein tyrosine phosphatases, a significant branch of phosphatases, are signaling enzymes responsible for the regulation of multifarious cellular processes, including cell growth, division, adhesion and motility progression throughout the entire life of normal cells [1,2]
Further analysis by Principal Component Analysis (PCA) demonstrated that the WPD loop in the apo Protein tyrosine phosphatase 1B (PTP1B) underwent more diverse conformations than that in the compound-3 bound PTP1B (Figure 1B), indicating the inherent flexibility of the WPD loop in the apo state
The difference was observed in the root mean square deviations (RMSD) calculation of Ca atoms (Figure 1C), the WPD loop randomly fluctuated in the apo state but maintained its open conformation in compound-3 bound state throughout the molecular dynamics (MD) simulations

Summary

Introduction

Protein tyrosine phosphatases (the PTP family), a significant branch of phosphatases, are signaling enzymes responsible for the regulation of multifarious cellular processes, including cell growth, division, adhesion and motility progression throughout the entire life of normal cells [1,2]. Protein tyrosine phosphatase 1B (PTP1B) expressed in the human body participates in selective dephosphorylation in various signal transduction pathways [5]. The highly conserved structural architecture in the active center of PTPs and low bioavailability presents a key challenge in the design and development of selective PTP inhibitors [8]. PTP1B shares 72% identity overall and 94% identity in the catalytic site residues with T-cell PTPs (TCPTP) [13]. In this context, most competitive inhibitors of PTP1B frequently have lethal adverse effects by affecting the normal function of TCPTP [7,14]

Methods

Results

Conclusion