Jasper Sandbox: Difference between revisions
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==Overview== | ==Overview== | ||
HRAS is an intercellular GTPase switch protein. It is directly involved with regulating cell growth, and is one of the first steps in the pathway. 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. HRAS is downstream from most RTK's, and the pathway culminates with the activation of MAP kinase. The protein SOS (son of sevenless) is necessary for HRAS to release GDP and become active. The SOS protein binds to a distal and active site on HRAS. It has also been shown that | HRAS is an intercellular GTPase switch protein. It is directly involved with regulating cell growth, and is one of the first steps in the pathway. 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. HRAS is downstream from most RTK's, and the pathway culminates with the activation of MAP kinase. The protein SOS (son of sevenless) is necessary for HRAS to release GDP and become active. The SOS protein binds to a distal and active site on HRAS. It has also been shown that prenylation of SOS is necessary for interactions with HRAS. | ||
==Mutations== | ==Mutations== | ||
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==About this Structure== | ==About 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 <scene name='5p21/Ligand_binding_site/1'>Walker motif</scene>. 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 <scene name='Jasper_Sandbox/Test1/2'>Gln61</scene> 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 | 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 <scene name='5p21/Ligand_binding_site/1'>Walker motif</scene>. 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 <scene name='Jasper_Sandbox/Test1/2'>Gln61</scene> 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 <scene name='Jasper_Sandbox/Test1/2'>Gln61</scene> and <scene name='Jasper_Sandbox/G63/1'>GLu63</scene>as activating species for in-line attack of water. Nucleophilic displacement is facilitated by hydrogen bonds from residues <scene name='Jasper_Sandbox/Thr35/1'>Thr35</scene>, <scene name='Jasper_Sandbox/Gly60/1'>Gly60</scene> and <scene name='Jasper_Sandbox/Lys16/1'>Lys16</scene>. | ||
5P21 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5P21 OCA]. | 5P21 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5P21 OCA]. | ||
==Reference== | ==Reference== | ||
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:[http://www.ncbi.nlm.nih.gov/pubmed/2196171 2196171] | 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:[http://www.ncbi.nlm.nih.gov/pubmed/2196171 2196171] | ||
Aoki, Y.; Niihori, T.; Kawame, H.; Kurosawa, K.; Ohashi, H.; Tanaka, Y.; Filocamo, M.; Kato, K.; Suzuki, Y.; Kure, S.; Matsubara, Y. : | |||
Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37: 1038-1040, 2005. | |||
Pechlivanis M, Ringel R, Popkirova B, Kuhlmann J. Prenylation of Ras facilitates hSOS1-promoted nucleotide exchange, upon Ras binding to the regulatory site | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 22:36:34 2008'' | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 22:36:34 2008'' | ||