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Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition
  • +5
  • Yang-Chun Ma,
  • Wen-Yu Yang,
  • Liang Zhou,
  • Jing-Wei Wu,
  • Wei-Ya Li,
  • Shan Du,
  • Ying Ma,
  • Run-Ling Wang
Yang-Chun Ma
Tianjin Medical University
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Wen-Yu Yang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
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Liang Zhou
Tianjin Medical University
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Jing-Wei Wu
Tianjin Medical University
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Wei-Ya Li
Tianjin Medical University
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Shan Du
Tianjin Medical University
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Ying Ma
Tianjin Medical University
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Run-Ling Wang
Tianjin Medical University
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Peer review status:UNDER REVIEW

21 Jul 2020Submitted to PROTEINS: Structure, Function, and Bioinformatics
23 Jul 2020Assigned to Editor
23 Jul 2020Submission Checks Completed
10 Aug 2020Reviewer(s) Assigned

Abstract

Protein Tyrosine Phosphatase non-receptor type 11 (PTPN11; encoding protein SHP2) is an important protein tyrosine phosphatase (PTP) in the human body and plays an important role in regulating cell proliferation and differentiation. Overexpression of SHP2 will promote the development of cancer diseases, so research on SHP2 inhibitors has become one of the popular targets for the treatment of cancer. Recent studies have shown that combining SHP099 (an allosteric site 1 inhibitor) with SHP844 (an allosteric site 2 inhibitor) will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamics simulations to explore the inhibition mechanism of SHP099 and SHP844 on SHP2 protein. The result shows that the interactions of allosteric site 1 (THR108-TRP112, LEU236-GLN245), allosteric site 2 (GLN79-GLN87, LEU262-GLN269), P-loop (HIS458-ARG465), and Q-loop (ARG501-THR507) are obviously enhanced in SHP2-SHP099-SHP844 system, which makes the fluctuation of residues more stable and the active site more difficult to be exposed. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that led to the SHP2 protein in auto-inhibition conformation. This study provides an idea that help people to understand the mechanism of inhibition of the combining SHP099 with SHP844 on the SHP2.