2GAQ

NMR SOLUTION STRUCTURE OF THE FRB DOMAIN OF mTOR

2GAQ の概要

• エントリーDOI: 10.2210/pdb2gaq/pdb
• 関連するPDBエントリー: 1AUE 1FAP 3FAP
• 分子名称: FKBP12-rapamycin complex-associated protein (1 entity in total)
• 機能のキーワード: four helical up and down bundle, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P42345
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12101.87

構造登録者

Leone, M.,Pellecchia, M. (登録日: 2006-03-09, 公開日: 2006-08-08, 最終更新日: 2024-05-29)

主引用文献

Leone, M.,Crowell, K.J.,Chen, J.,Jung, D.,Chiang, G.G.,Sareth, S.,Abraham, R.T.,Pellecchia, M.
The FRB Domain of mTOR: NMR Solution Structure and Inhibitor Design.
Biochemistry, 45:10294-10302, 2006

PubMed Abstract: The mammalian target of rapamycin (mTOR) is a protein that is intricately involved in signaling pathways controlling cell growth. Rapamycin is a natural product that binds and inhibits mTOR function by interacting with its FKBP-rapamycin-binding (FRB) domain. Here we report on the NMR solution structure of FRB and on further studies aimed at the identification and characterization of novel ligands that target the rapamycin binding pocket. The biological activity of the ligands, and that of rapamycin in the absence of FKBP12, was investigated by assaying the kinase activity of mTOR. While we found that rapamycin binds the FRB domain and inhibits the kinase activity of mTOR even in the absence of FKBP12 (in the low micromolar range), our most potent ligands bind to FRB with similar binding affinity but inhibit the kinase activity of mTOR at much higher concentrations. However, we have also identified one low-affinity compound that is also capable of inhibiting mTOR. Hence, we have identified compounds that can directly mimic rapamycin or can dissociate the FRB binding from the inhibition of the catalytic activity of mTOR. As such, these ligands could be useful in deciphering the complex regulation of mTOR in the cell and in validating the FRB domain as a possible target for the development of novel therapeutic compounds.

PubMed: 16922504
DOI: 10.1021/bi060976+

実験手法

SOLUTION NMR