3OIU

H-RasQ61L with allosteric switch in the "on" state

3OIU の概要

• エントリーDOI: 10.2210/pdb3oiu/pdb
• 関連するPDBエントリー: 3OIV 3OIW
• 分子名称: GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: oncogene gtp-binding nucleotide-binding, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane. Isoform 2: Nucleus: P01112
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19610.31

構造登録者

Buhrman, G.,Mattos, C. (登録日: 2010-08-20, 公開日: 2010-12-08, 最終更新日: 2024-02-21)

主引用文献

Buhrman, G.,Kumar, V.S.,Cirit, M.,Haugh, J.M.,Mattos, C.
Allosteric Modulation of Ras-GTP Is Linked to Signal Transduction through RAF Kinase.
J.Biol.Chem., 286:3323-3331, 2011

PubMed Abstract: Ras is a key signal transduction protein in the cell. Mutants of Gly(12) and Gln(61) impair GTPase activity and are found prominently in cancers. In wild type Ras-GTP, an allosteric switch promotes disorder to order transition in switch II, placing Gln(61) in the active site. We show that the "on" and "off" conformations of the allosteric switch can also be attained in RasG12V and RasQ61L. Although both mutants have similarly impaired active sites in the on state, RasQ61L stabilizes an anti-catalytic conformation of switch II in the off state of the allosteric switch when bound to Raf. This translates into more potent activation of the MAPK pathway involving Ras, Raf kinase, MEK, and ERK (Ras/Raf/MEK/ERK) in cells transfected with RasQ61L relative to RasG12V. This differential is not observed in the Raf-independent pathway involving Ras, phosphoinositide 3-kinase (PI3K), and Akt (Ras/PI3K/Akt). Using a combination of structural analysis, hydrolysis rates, and experiments in NIH-3T3 cells, we link the allosteric switch to the control of signaling in the Ras/Raf/MEK/ERK pathway, supporting a GTPase-activating protein-independent model for duration of the Ras-Raf complex.

PubMed: 21098031
DOI: 10.1074/jbc.M110.193854

実験手法

X-RAY DIFFRACTION (1.32 Å)