4JT6

structure of mTORDeltaN-mLST8-PI-103 complex

4JT6 の概要

• エントリーDOI: 10.2210/pdb4jt6/pdb
• 関連するPDBエントリー: 4JSN 4JSP 4JSV 4JSX 4JT5
• 分子名称: mTOR, mLST8, 3-(4-MORPHOLIN-4-YLPYRIDO[3',2':4,5]FURO[3,2-D]PYRIMIDIN-2-YL)PHENOL (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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 (By similarity): Q9BVC4
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 341817.39

構造登録者

Pavletich, N.P.,Yang, H. (登録日: 2013-03-22, 公開日: 2013-05-08, 最終更新日: 2024-02-28)

主引用文献

Yang, H.,Rudge, D.G.,Koos, J.D.,Vaidialingam, B.,Yang, H.J.,Pavletich, N.P.
mTOR kinase structure, mechanism and regulation.
Nature, 497:217-223, 2013

PubMed Abstract: 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.

PubMed: 23636326
DOI: 10.1038/nature12122

実験手法

X-RAY DIFFRACTION (3.6 Å)