Exploring the effect of N308D mutation on protein tyrosine phosphatase‐2 cause gain‐of‐function activity by a molecular dynamics study

2018 ◽  
Vol 120 (4) ◽  
pp. 5949-5961 ◽  
Author(s):  
Ying‐Zhan Sun ◽  
Xiu‐Bo Chen ◽  
Rui‐Rui Wang ◽  
Wei‐Ya Li ◽  
Ying Ma
Keyword(s):  
Molecular Dynamics ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Gain Of Function ◽  
Protein Tyrosine ◽  
Function Activity

scholarly journals Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Xi Chen ◽  
Xia Liu ◽  
Qiang Gan ◽  
Changgen Feng ◽  
Qian Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Selective Binding ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Dynamics Simulations

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.

scholarly journals Exploring the Allosteric Mechanism of Src Homology-2 Domain-Containing Protein Tyrosine Phosphatase 2 (SHP2) by Molecular Dynamics Simulations

2020 ◽  
Vol 8 ◽  
Author(s):  
Quan Wang ◽  
Wen-Cheng Zhao ◽  
Xue-Qi Fu ◽  
Qing-Chuan Zheng
Keyword(s):  
Molecular Dynamics ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Allosteric Regulation ◽  
Sh2 Domain ◽  
Regulation Mechanism ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Activated State ◽  
Src Homology

The Src homology-2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2, encoded by PTPN11) is a critical allosteric phosphatase for many signaling pathways. Programmed cell death 1 (PD-1) could be phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and can bind to SHP2 to initiate T cell inactivation. Although the interaction of SHP2-PD-1 plays an important role in the immune process, the complex structure and the allosteric regulation mechanism remain unknown. In this study, molecular dynamics (MD) simulations were performed to study the binding details of SHP2 and PD-1, and explore the allosteric regulation mechanism of SHP2. The results show that ITIM has a preference to bind to the N-SH2 domain and ITSM has almost the same binding affinity to the N-SH2 and C-SH2 domain. Only when ITIM binds to the N-SH2 domain and ITSM binds to the C-SH2 domain can the full activation of SHP2 be obtained. The binding of ITIM and ITSM could change the motion mode of SHP2 and switch it to the activated state.

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