mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain
By Haijuan Yang, Derek G. Rudge, J. D. Koos, B. Vaidialingam, Hyo J. Yang, N. Pavletich. Nature, 2013
844 citations recorded by the source corpus.
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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/28775ab22c4256634357897a0c38116b343667c3
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Citations in the corpus
- Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “22,29 The structural architect of mTORC1 de fi nes the complex and symmetric organization of Raptor, PRAS40, DEPTOR, and mLST8 (G β L) as its major components along with centrally located mTOR protein.”
- The Neurology of mTOR (2014, positive): “by observations that high concentrations of rapamycin directly interact with mTOR within the FKBP12-rapamycin binding domain (FRB) (Figure 1A; Yang et al., 2013).”
- Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, neutral): “*Author for correspondence (wei.cui@imperial.ac.uk) J.S.L.Y., 0000-0001-5203-3603; W.C., 0000-0003-2019-380X D E V E LO P M E N T (Yang et al., 2013; Liu et al., 2015).”