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Study on the allosteric activation mechanism of SHP2 via elastic network models and neural relational inference molecular dynamics simulation.
- Source :
- Physical Chemistry Chemical Physics (PCCP); 9/21/2023, Vol. 25 Issue 35, p23588-23601, 14p
- Publication Year :
- 2023
-
Abstract
- As a ubiquitous protein tyrosine phosphatase, SHP2 is involved in PD-1/PD-L1 mediated tumor immune escape and undergoes substantial conformational changes. Therefore, it is considered an ideal target for tumor intervention. However, the allosteric mechanisms of SHP2 binding PD-1 intracellular ITIM/ITSM phosphopeptides remain unclear, which greatly hinders the development of novel structure-based anticancer allosteric inhibitors. In this work, the open and closed structural models of SHP2 are first constructed based on this knowledge; next their motion modes are investigated via elastic network models such as the Gaussian network model (GNM), anisotropic network model (ANM) and adaptive anisotropic network model (aANM); and finally, a possible allosteric signaling pathway is proposed using a neural relational inference molecular dynamics (NRI-MD) simulation embedded with an artificial intelligence (AI) strategy. In GNM and ANM, the N-SH2, C-SH2 and PTP domains all exhibit distinct dynamics partitions, and the N-SH2/C-SH2 regions show a rigid rotation relative to PTP. According to a series of intermediate snapshots given by aANM, N-SH2 is first identified with pY223 specifically, inducing a D'E-loop to change from β-sheets to random coils, and then, C-SH2 serves as a fulcrum to drive N-SH2 to rotate 110° completely away from the original active sites of PTP. Finally, a possible allosteric signaling-transfer path for SHP2, namely R220-R138-T108-R32, is proposed based on NRI-MD sampling. This work provides a possible allosteric mechanism of SHP2, which is helpful for the following design of novel allosteric inhibitors and is expected to be used in clinical synergies with PD-1 monoclonal antibody. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14639076
- Volume :
- 25
- Issue :
- 35
- Database :
- Complementary Index
- Journal :
- Physical Chemistry Chemical Physics (PCCP)
- Publication Type :
- Academic Journal
- Accession number :
- 171923620
- Full Text :
- https://doi.org/10.1039/d3cp02795c