6BSX

CRYSTAL STRUCTURE OF RHEB IN COMPLEX WITH COMPOUND 1 AT 1.65A RESOLUTION

6BSX の概要

• エントリーDOI: 10.2210/pdb6bsx/pdb
• 関連するPDBエントリー: 1XTQ
• 分子名称: GTP-binding protein Rheb, MAGNESIUM ION, ACETATE ION, ... (7 entities in total)
• 機能のキーワード: mtorc1 g-protein, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system ; Lipid-anchor ; Cytoplasmic side : Q15382
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 84003.51

構造登録者

Mahoney, S.J. (登録日: 2017-12-04, 公開日: 2018-02-28, 最終更新日: 2023-10-04)

主引用文献

Mahoney, S.J.,Narayan, S.,Molz, L.,Berstler, L.A.,Kang, S.A.,Vlasuk, G.P.,Saiah, E.
A small molecule inhibitor of Rheb selectively targets mTORC1 signaling.
Nat Commun, 9:548-548, 2018

PubMed Abstract: The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.

PubMed: 29416044
DOI: 10.1038/s41467-018-03035-z

実験手法

X-RAY DIFFRACTION (1.65 Å)