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| - | [[Image:1clu.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1clu| PDB=1clu | SCENE= }} | | {{STRUCTURE_1clu| PDB=1clu | SCENE= }} |
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| - | '''H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP'''
| + | ===H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP=== |
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| - | ==Overview==
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| - | Interest in the guanosine triphosphatase (GTPase) reaction of Ras as a molecular drug target stems from the observation that, in a large number of human tumors, Ras is characteristically mutated at codons 12 or 61, more rarely 13. Impaired GTPase activity, even in the presence of GTPase activating proteins, has been found to be the biochemical reason behind the oncogenicity of most Gly12/Gln61 mutations, thus preventing Ras from being switched off. Therefore, these oncogenic Ras mutants remain constitutively activated and contribute to the neoplastic phenotype of tumor cells. Here, we show that the guanosine 5'-triphosphate (GTP) analogue diaminobenzophenone-phosphoroamidate-GTP (DABP-GTP) is hydrolyzed by wild-type Ras but more efficiently by frequently occurring oncogenic Ras mutants, to yield guanosine 5'-diphosphate-bound inactive Ras and DABP-Pi. The reaction is independent of the presence of Gln61 and is most dramatically enhanced with Gly12 mutants. Thus, the defective GTPase reaction of the oncogenic Ras mutants can be rescued by using DABP-GTP instead of GTP, arguing that the GTPase switch of Ras is not irreversibly damaged. An exocyclic aromatic amino group of DABP-GTP is critical for the reaction and bypasses the putative rate-limiting step of the intrinsic Ras GTPase reaction. The crystal structures of Ras-bound DABP-beta,gamma-imido-GTP show a disordered switch I and identify the Gly12/Gly13 region as the hydrophobic patch to accommodate the DABP-moiety. The biochemical and structural studies help to define the requirements for the design of anti-Ras drugs aimed at the blocked GTPase reaction.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10359839}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10359839 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10359839}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Gtp hydrolase]] | | [[Category: Gtp hydrolase]] |
| | [[Category: Signal transduction]] | | [[Category: Signal transduction]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:52:18 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 20:55:26 2008'' |
Revision as of 17:55, 30 June 2008
Template:STRUCTURE 1clu
H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP
Template:ABSTRACT PUBMED 10359839
About this Structure
1CLU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Guanosine triphosphatase stimulation of oncogenic Ras mutants., Ahmadian MR, Zor T, Vogt D, Kabsch W, Selinger Z, Wittinghofer A, Scheffzek K, Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7065-70. PMID:10359839
Page seeded by OCA on Mon Jun 30 20:55:26 2008
