PMID- 23636326
OWN - NLM
STAT- MEDLINE
DCOM- 20130530
LR  - 20220129
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 497
IP  - 7448
DP  - 2013 May 9
TI  - mTOR kinase structure, mechanism and regulation.
PG  - 217-23
LID - 10.1038/nature12122 [doi]
AB  - 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.
FAU - Yang, Haijuan
AU  - Yang H
AD  - Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New 
      York 10065, USA.
FAU - Rudge, Derek G
AU  - Rudge DG
FAU - Koos, Joseph D
AU  - Koos JD
FAU - Vaidialingam, Bhamini
AU  - Vaidialingam B
FAU - Yang, Hyo J
AU  - Yang HJ
FAU - Pavletich, Nikola P
AU  - Pavletich NP
LA  - eng
SI  - PDB/4JSN
SI  - PDB/4JSP
SI  - PDB/4JSV
SI  - PDB/4JSX
SI  - PDB/4JT5
SI  - PDB/4JT6
GR  - HHMI_/Howard Hughes Medical Institute/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130501
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 
      (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Furans)
RN  - 0 (Indoles)
RN  - 0 (MLST8 protein, human)
RN  - 0 (Naphthyridines)
RN  - 0 (PI103)
RN  - 0 (Purines)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (mTOR Associated Protein, LST8 Homolog)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - H5669VNZ7V (PP242)
RN  - I38ZP9992A (Magnesium)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Nature. 2013 May 9;497(7448):193-4. PMID: 23636322
MH  - Adaptor Proteins, Signal Transducing/chemistry/metabolism
MH  - Adenosine Triphosphate/chemistry/metabolism
MH  - Catalytic Domain/drug effects
MH  - Crystallography, X-Ray
MH  - Furans/chemistry/pharmacology
MH  - Humans
MH  - Indoles/chemistry/metabolism/pharmacology
MH  - Magnesium/chemistry/metabolism
MH  - Models, Molecular
MH  - Naphthyridines/chemistry/metabolism/pharmacology
MH  - Protein Structure, Tertiary/drug effects
MH  - Purines/chemistry/metabolism/pharmacology
MH  - Pyridines/chemistry/pharmacology
MH  - Pyrimidines/chemistry/pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Sirolimus/chemistry/metabolism/pharmacology
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism
MH  - Tacrolimus Binding Protein 1A/chemistry/metabolism/pharmacology
MH  - mTOR Associated Protein, LST8 Homolog
PMC - PMC4512754
MID - NIHMS461183
COIS- The authors declare no competing financial interests.
EDAT- 2013/05/03 06:00
MHDA- 2013/06/01 06:00
PMCR- 2015/07/23
CRDT- 2013/05/03 06:00
PHST- 2013/01/02 00:00 [received]
PHST- 2013/03/26 00:00 [accepted]
PHST- 2013/05/03 06:00 [entrez]
PHST- 2013/05/03 06:00 [pubmed]
PHST- 2013/06/01 06:00 [medline]
PHST- 2015/07/23 00:00 [pmc-release]
AID - nature12122 [pii]
AID - 10.1038/nature12122 [doi]
PST - ppublish
SO  - Nature. 2013 May 9;497(7448):217-23. doi: 10.1038/nature12122. Epub 2013 May 1.