Structure of the Human mTOR Complex I and Its Implications for Rapamycin Inhibition

被引：337

作者：

Yip, Calvin K. ^{[2
]}

Murata, Kazuyoshi ^{[1
]}

Walz, Thomas ^{[2
,3
]}

Sabatini, David M. ^{[1
,4
,5
,6
]}

Kang, Seong A. ^{[1
,4
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA

[4] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[5] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Seven Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA

来源：

MOLECULAR CELL | 2010年 / 38卷 / 05期

基金：

加拿大健康研究院;

关键词：

MAMMALIAN TARGET; PROTEIN-KINASE; CELL-GROWTH; RAPTOR; DNA; INSULIN; BINDING; TOR; PHOSPHORYLATION; TRANSLATION;

D O I：

10.1016/j.molcel.2010.05.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. The dimeric interfaces are formed by interlocking interactions between the mTOR and raptor subunits. Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1-mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms.

引用

页码：768 / 774

页数：7

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