5WBU

Crystal structure of mTOR(deltaN)-mLST8-PRAS40(alpha-helix & beta-strand) complex

5WBU の概要

• エントリーDOI: 10.2210/pdb5wbu/pdb
• 分子名称: Serine/threonine-protein kinase mTOR, Target of rapamycin complex subunit LST8, Proline-rich AKT1 substrate 1 (3 entities in total)
• 機能のキーワード: complex, frb, wd40, pras40, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P42345; Cytoplasm : Q9BVC4; Cytoplasm, cytosol : Q96B36
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 381231.46

構造登録者

Pavletich, N.P.,Yang, H. (登録日: 2017-06-29, 公開日: 2017-12-20, 最終更新日: 2023-10-04)

主引用文献

Yang, H.,Jiang, X.,Li, B.,Yang, H.J.,Miller, M.,Yang, A.,Dhar, A.,Pavletich, N.P.
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.
Nature, 552:368-373, 2017

PubMed Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.

PubMed: 29236692
DOI: 10.1038/nature25023

実験手法

X-RAY DIFFRACTION (3.42 Å)