3oiw

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

spinqualitylabelsall models 3oiw, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3oiw is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, CA, GNP, MG Related: 3oiu, 3oiv Gene: HRAS, HRAS1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [RASH_HUMAN] Defects in HRAS are the cause of faciocutaneoskeletal syndrome (FCSS) [MIM:218040]. A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]. CMEMS is a variant of Costello syndrome. Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. Defects in HRAS are a cause of susceptibility to bladder cancer (BLC) [MIM:109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC). Defects in HRAS are the cause of Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200]. A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis. Function [RASH_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMed Ras is a key signal transduction protein in the cell. Mutants of G12 and Q61 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 Q61 in the active site. We show that the on and off conformations of the allosteric switch can also be attained in RasG12V and RasQ61L. While 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 mitogen activated protein kinase pathway involving Ras, Raf kinase, extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase (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 GAP-independent model for duration of the Ras/Raf complex. Allosteric modulation of Ras-GTP is linked to signal transduction through Raf kinase.,Buhrman G, Kumar VS, Cirit M, Haugh JM, Mattos C J Biol Chem. 2010 Nov 22. PMID:21098031 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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