蛋白激酶结构域
PI3K/AKT/mTOR通路
激酶
活动站点
细胞生物学
蛋白激酶A
生物
雷帕霉素的作用靶点
结合位点
生物化学
磷酸化
化学
信号转导
酶
基因
突变体
作者
Haijuan Yang,Derek G. Rudge,Joseph D. Koos,Bhamini Vaidialingam,Hyo J. Yang,Nikola P. Pavletich
出处
期刊:Nature
[Springer Nature]
日期:2013-05-01
卷期号:497 (7448): 217-223
被引量:917
摘要
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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