7Z38

Structure of the RAF1-HSP90-CDC37 complex (RHC-I)

7Z38 の概要

• エントリーDOI: 10.2210/pdb7z38/pdb
• 関連するPDBエントリー: 7Z37
• EMDBエントリー: 14472 14473
• 分子名称: Heat shock protein HSP 90-beta, RAF proto-oncogene serine/threonine-protein kinase, Hsp90 co-chaperone Cdc37, ... (5 entities in total)
• 機能のキーワード: raf1-hsp90-cdc37, complex, proto-oncogene, transferase, serine/threonine kinase, cancer, chaperone
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 290751.00

構造登録者

Mesa, P.,Garcia-Alonso, S.,Barbacid, M.,Montoya, G. (登録日: 2022-03-01, 公開日: 2022-09-14, 最終更新日: 2024-10-09)

主引用文献

Garcia-Alonso, S.,Mesa, P.,Ovejero, L.P.,Aizpurua, G.,Lechuga, C.G.,Zarzuela, E.,Santiveri, C.M.,Sanclemente, M.,Munoz, J.,Musteanu, M.,Campos-Olivas, R.,Martinez-Torrecuadrada, J.,Barbacid, M.,Montoya, G.
Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
Mol.Cell, 82:3438-3452.e8, 2022

PubMed Abstract: RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.

PubMed: 36055235
DOI: 10.1016/j.molcel.2022.08.012

実験手法

ELECTRON MICROSCOPY (3.16 Å)