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REFINED CRYSTAL STRUCTURE OF THE TRIPHOSPHATE CONFORMATION OF H-RAS P21 AT 1.35 ANGSTROMS RESOLUTION: IMPLICATIONS FOR THE MECHANISM OF GTP HYDROLYSIS

spinqualitylabelsall models PDB ID 5p21 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
5p21, resolution 1.35Å ()
Ligands:	,
Structural annotation: Resources: CATH : 5P21000 InterPro : Ipr005225, Ipr013753, Ipr001806, Ipr003577, Ipr015592 Pfam : PF00071 SCOP : d5p21__ UniProt : P01112
Functional annotation: Cellular component: cytoplasm membrane plasma membrane Golgi apparatus intracellular Biological process: small GTPase mediated signal transduction cell surface receptor linked signal transduction chemotaxis signal transduction organ morphogenesis Molecular function: protein binding nucleotide binding protein C-terminus binding GTP binding
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

OverviewOverview

HRAS is an intercellular GTPase switch protein. It has two forms, an active form in which it is bound to GTP and an inactive form in which it is bound to GDP. The protein SOS (son of sevenless) is necessary for HRAS to release GDP and become active. Ras is downstream from most RTK's, and the pathway culminates with the activation of MAP kinase.

MutationsMutations

Mutations in the HRAS can lead to the development of Costello syndrome and bladder cancer. Costello syndrome is a genetic disorder in which infants can be born mentally retarded, commonly with loose folds of skin and very flexible joints. The most common mutation is the replacement of glycine with serine at G12S, although five mutations have been linked to the disorder. The mutation leads to HRAS that is unable to enter the inactive form, and thus leads to uncontrolled cell growth. The mutation of HRAS linked with bladder cancer is at G12V, where a valine replaces a glycine. Like the mutation in Costello syndrome, this mutation results in HRAS proteins to be constantly on which leads to uncontrolled growth.

About this StructureAbout this Structure

The crystal structure of the H-ras oncogene protein p21 complexed to the slowly hydrolysing GTP analogue GppNp has been determined at 1.35 A resolution. 211 water molecules have been built into the electron density. The structure has been refined to a final R-factor of 19.8% for all data between 6 A and 1.35 A. The binding sites of the nucleotide and the magnesium ion are revealed in high detail and consists of a characteristic . For the stretch of amino acid residues 61-65, the temperature factors of backbone atoms are four times the average value of 16.1 A2 due to the multiple conformations. In one of these conformations, the side chain of makes contact with a water molecule, which is perfectly placed to be the nucleophile attacking the gamma-phosphate of GTP. Based on this observation, we propose a mechanism for GTP hydrolysis involving mainly Gln61 and Glu63 as activating species for in-line attack of water. Nucleophilic displacement is facilitated by hydrogen bonds from residues Thr35, Gly60 and Lys16. A mechanism for rate enhancement by GAP is also proposed.

5P21 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis., Pai EF, Krengel U, Petsko GA, Goody RS, Kabsch W, Wittinghofer A, EMBO J. 1990 Aug;9(8):2351-9. PMID:2196171 Page seeded by OCA on Sun May 4 22:36:34 2008