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

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...

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Main Authors: Shuai Li, Jingmiao Zhang, Shaoyong Lu, Wenkang Huang, Lv Geng, Qiancheng Shen, Jian Zhang
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4022711?pdf=render
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spelling doaj-e7cc7f80d0da45a9abafa06c7d42aca82020-11-24T21:51:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9766810.1371/journal.pone.0097668The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.Shuai LiJingmiao ZhangShaoyong LuWenkang HuangLv GengQiancheng ShenJian ZhangAs 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.http://europepmc.org/articles/PMC4022711?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Shuai Li
Jingmiao Zhang
Shaoyong Lu
Wenkang Huang
Lv Geng
Qiancheng Shen
Jian Zhang
spellingShingle Shuai Li
Jingmiao Zhang
Shaoyong Lu
Wenkang Huang
Lv Geng
Qiancheng Shen
Jian Zhang
The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
PLoS ONE
author_facet Shuai Li
Jingmiao Zhang
Shaoyong Lu
Wenkang Huang
Lv Geng
Qiancheng Shen
Jian Zhang
author_sort Shuai Li
title The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
title_short The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
title_full The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
title_fullStr The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
title_full_unstemmed The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
title_sort mechanism of allosteric inhibition of protein tyrosine phosphatase 1b.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2014-01-01
description 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.
url http://europepmc.org/articles/PMC4022711?pdf=render
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