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2013 ; 497
(7448
): 217-23
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mTOR kinase structure, mechanism and regulation
#MMPMID23636326
Yang H
; Rudge DG
; Koos JD
; Vaidialingam B
; Yang HJ
; Pavletich NP
Nature
2013[May]; 497
(7448
): 217-23
PMID23636326
show ga
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.
|Adaptor Proteins, Signal Transducing/chemistry/metabolism
[MESH]
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