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Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.

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Pádua RAP, Sun Y, Marko I, Pitsawong W, Stiller JB, Otten R, Kern D
OpenAccess logo Nat Commun 9 4507 (2018)
Related entries: 6cmp, 6cmr, 6cms

Cited: 46 times
EuropePMC logo PMID: 30375376

Abstract

Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K's much higher activity, demands significantly greater SHP099 concentrations to restore wild-type  activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.

Articles - 6cmq mentioned but not cited (3)

  1. Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2. Pádua RAP, Sun Y, Marko I, Pitsawong W, Stiller JB, Otten R, Kern D. Nat Commun 9 4507 (2018)
  2. Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases. Hong SH, Xi SY, Johns AC, Tang LC, Li A, Hum MN, Chartier CA, Jovanovic M, Shah NH. Chembiochem 24 e202200706 (2023)
  3. Monobody Inhibitor Selective to the Phosphatase Domain of SHP2 and its Use as a Probe for Quantifying SHP2 Allosteric Regulation. Sha F, Kurosawa K, Glasser E, Ketavarapu G, Albazzaz S, Koide A, Koide S. J Mol Biol 435 168010 (2023)


Reviews citing this publication (13)

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  2. Harnessing Conformational Plasticity to Generate Designer Enzymes. Crean RM, Gardner JM, Kamerlin SCL. J Am Chem Soc 142 11324-11342 (2020)
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  4. Mechanism of activation and the rewired network: New drug design concepts. Nussinov R, Zhang M, Maloney R, Tsai CJ, Yavuz BR, Tuncbag N, Jang H. Med Res Rev 42 770-799 (2022)
  5. Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs. Nussinov R, Zhang M, Maloney R, Liu Y, Tsai CJ, Jang H. J Mol Biol 434 167569 (2022)
  6. Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy. Pan J, Zhou L, Zhang C, Xu Q, Sun Y. Signal Transduct Target Ther 7 177 (2022)
  7. Strategies to overcome drug resistance using SHP2 inhibitors. Liu M, Gao S, Elhassan RM, Hou X, Fang H. Acta Pharm Sin B 11 3908-3924 (2021)
  8. Precision targeted therapy for EGFR mutation-positive NSCLC: Dilemmas and coping strategies. Meng Y, Bai R, Cui J. Thorac Cancer 14 1121-1134 (2023)
  9. SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment. Sodir NM, Pathria G, Adamkewicz JI, Kelley EH, Sudhamsu J, Merchant M, Chiarle R, Maddalo D. Cancer Discov 13 2339-2355 (2023)
  10. New prospectives on treatment opportunities in RASopathies. Gelb BD, Yohe ME, Wolf C, Andelfinger G. Am J Med Genet C Semin Med Genet 190 541-560 (2022)
  11. Novel therapeutic perspectives in Noonan syndrome and RASopathies. Saint-Laurent C, Mazeyrie L, Yart A, Edouard T. Eur J Pediatr (2023)
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  13. Setting sail: Maneuvering SHP2 activity and its effects in cancer. Welsh CL, Allen S, Madan LK. Adv Cancer Res 160 17-60 (2023)

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