Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
Open accessAbstract
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.
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SHP2 is involved in regulation of multiple signaling pathways, including RAS-MAPK, PI3K-AKT and JAK-STAT.
“As protein tyrosine phosphorylation plays an essential role in multiple intracellular processes, SHP2 is involved in the regulation of multiple signaling pathways, including those involved in cancer cells, such as RAS-MAPK, PI3K-AKT and JAK-STAT pathways.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [262]
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- Authors
- Pádua, R. A. P., Sun, Y., Marko, I., Pitsawong, W., Stiller, J. B., Otten, R., & Kern, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kern, Dorothee
- Venue
- Nature Communications
- Published
- 2018-10-30
- Volume
- 9
- Issue
- 1
- Pages
- 4507-4507
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6207724
- OpenAlex
- W2898440791
- Cited by
- 133
- References
- 79
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 18 · 2023: 21 · 2022: 18 · 2021: 20 · 2020: 17 · 2019: 7
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Howard Hughes Medical Institute (DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, 76SF00515, DE–AC02–76SF00515, 05CH11231, P41GM103393, DE AC02 05CH11231, AC02‐76SF00515, DE-AC02-)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (DE-AC02-05CH11231)
- National Institutes of Health (DE-AC02–05CH11231, DE-AC02-76SF00515, GM100966)
- Office of Science (AC02-76SF00515, P41GM103393, DEAC02–05CH11231, AC02-05CH11231, DE-AC02-76SF0051 5, DE-AC02, 05CH11231, 76SF00515)
- Ciência sem Fronteiras
- National Institute of General Medical Sciences (T32GM007596, DE-AC02-05CH11231, DE-AC02-76SF00515, R01GM100966, P41GM103393)
- National Institute of Biomedical Imaging and Bioengineering (T32EB009419)
- Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., P41GM103393, AC02–05CH11231, 76SF00515, AC02-76SF00515, DE-AC-02-76SF00515)
- Biological and Environmental Research (05CH11231, P41 GM103393, DE-AC02 − 05CH11231, DE- AC0276SF00515, AC02-05CH11231)
- SLAC National Accelerator Laboratory (DE-AC02-05-CH11231, DEAC02−76SF00515, AC02‐76SF00515, P41GM103393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SHP2, protein tyrosine phosphatase, oncogenic mutations, allosteric inhibition, SHP099, conformational selection, open and closed conformations, WPD loop, energy landscape, drug binding kinetics, cancer
- MeSH terms
- Allosteric Regulation, Humans, Mutation, Magnetic Resonance Spectroscopy, Piperidines, Protein Conformation, Pyrimidines, Crystallography, X-Ray, Protein Tyrosine Phosphatase, Non-Receptor Type 11
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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