3OIW

H-RasG12V with allosteric switch in the "on" state

Summary for 3OIW

• Entry DOI: 10.2210/pdb3oiw/pdb
• Related: 3OIU 3OIV
• Descriptor: GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: oncogene gtp-binding nucleotide-binding, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane. Isoform 2: Nucleus: P01112
• Total number of polymer chains: 1
• Total formula weight: 19667.36

Authors

Kumar, S.,Buhrman, G.,Mattos, C. (deposition date: 2010-08-20, release date: 2010-12-08, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.3 Å)