mTOR kinase structure, mechanism and regulation
Open accessAbstract
The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.
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The mTORC1 crystal structure revealed that the kinase domain exhibited a classical bilobed structure, just as in the PI3K family, and the PIKK-specific FAT domain encircles the kinase domain.
“The crystal structure revealed that the kinase domain exhibited a classical bilobed structure, just as in the PI3K family, and the PIKK-specific FAT domain encircles the kinase domain, raising the possibility that interaction of regulatory proteins with this region will allosterically impact the kinase domain structure as well.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yang et al., 2013
The structure of the mTORC1 core, consisting of an mTOR mLST8 "FATKIN" unit, was solved in 2013 by Yang and colleagues, providing the first structural data on the kinase and enabling a molecular-level understanding of kinase inhibition by rapamycin.
“The structure of the mTORC1 core, consisting of an mTOR mLST8 “FATKIN” unit, was solved in 2013 by Yang and colleagues, providing the first structural data on the kinase and enabling a molecular-level understanding of kinase inhibition by rapamycin (Yang et al., 2013).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yang et al., 2013
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- Authors
- Yang, H., Rudge, D. G., Koos, J. D., Vaidialingam, B., Yang, H. J., & Pavletich, N. P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Pavletich, Nikola P.
- Venue
- Nature
- Published
- 2013-05
- Volume
- 497
- Issue
- 7448
- Pages
- 217-223
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4512754
- OpenAlex
- W2168180694
- Cited by
- 1,075
- References
- 55
- Citations by year
- 2026: 62 · 2025: 80 · 2024: 90 · 2023: 90 · 2022: 107 · 2021: 90 · 2020: 82 · 2019: 89 · 2018: 73 · 2017: 74 · 2016: 71 · 2015: 75 · 2014: 61 · 2013: 29
- FWCI
- 36.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTOR kinase, mLST8, rapamycin, FKBP12, FRB domain, ATP-competitive inhibitors, substrate recruitment, kinase activation mechanism, cell growth regulation
- MeSH terms
- mTOR Associated Protein, LST8 Homolog, Adenosine Triphosphate, Furans, Humans, Indoles, Magnesium, Models, Molecular, Naphthyridines, Purines, Pyridines, Pyrimidines, Structure-Activity Relationship, Protein Structure, Tertiary, Crystallography, X-Ray, Sirolimus, Catalytic Domain, Tacrolimus Binding Protein 1A, Ribosomal Protein S6 Kinases, 70-kDa, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases
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