mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs
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Abstract
mTOR plays a crucial role in PI3K/AKT/mTOR signaling. We hypothesized that mTOR activation mechanisms driving oncogenesis can advise effective therapeutic designs. To test this, we combined cancer genomic analysis with extensive molecular dynamics simulations of mTOR oncogenic variants. We observed that conformational changes within mTOR kinase domain are associated with multiple mutational activation events. The mutations disturb the α-packing formed by the kαAL, kα3, kα9, kα9b, and kα10 helices in the kinase domain creating cryptic pocket. Its opening correlates with opening of the catalytic cleft, including active site residues realignment, favoring catalysis. The cryptic pocket created by disrupted α-packing coincides with the allosteric pocket in PI3Kα can be harmoniously fitted by the PI3Kα allosteric inhibitor RLY-2608, suggesting that analogous drugs designed based on RLY-2608 can restore the packed α-structure, resulting in mTOR inactive conformation. Our results exemplify that knowledge of detailed kinase activation mechanisms can inform innovative allosteric inhibitor development.
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Cites
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- Authors
- Liu, Y., Zhang, W., Jang, H., & Nussinov, R.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- Tel Aviv University (IL)
- Corresponding author
- Nussinov, Ruth
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2025-01-10
- Volume
- 65
- Issue
- 2
- Pages
- 966-980
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- PMC
- PMC12091942
- OpenAlex
- W4406242429
- Cited by
- 10
- References
- 6
- Citations by year
- 2026: 7 · 2025: 3
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Chemical Information and Modeling (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Division of Cancer Prevention, National Cancer Institute (HHSN261201500003I)
- Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- mTOR, cryptic pocket, allosteric inhibition, PI3Kα, kinase domain conformation, alpha-helix packing, catalytic cleft, PI3K/AKT/mTOR pathway, molecular dynamics simulation, cancer genomics
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, MTOR Inhibitors, Allosteric Regulation, Allosteric Site, Enzyme Activation, Humans, Mutation, Protein Conformation, Drug Design, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Molecular Dynamics Simulation, TOR Serine-Threonine Kinases
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