MTOR kinase structure, mechanism and regulation Journal Article


Authors: Yang, H.; Rudge, D. G.; Koos, J. D.; Vaidialingam, B.; Yang, H. J.; Pavletich, N. P.
Article Title: MTOR kinase structure, mechanism and regulation
Abstract: 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. © 2013 Macmillan Publishers Limited. All rights reserved.
Journal Title: Nature
Volume: 497
Issue: 7448
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2013-05-09
Start Page: 217
End Page: 223
Language: English
DOI: 10.1038/nature12122
PROVIDER: scopus
PUBMED: 23636326
PMCID: PMC4512754
DOI/URL:
Notes: - Cited By (since 1996):1 - "Export Date: 3 June 2013" - "CODEN: NATUA" - "Source: Scopus"
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MSK Authors
  1. Haijuan Yang
    12 Yang
  2. Derek Rudge
    2 Rudge
  3. Joseph Douglas Koos
    1 Koos
  4. Hyo Jung Yang
    3 Yang