1clu

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[[Image:1clu.gif|left|200px]]<br /><applet load="1clu" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1clu.gif|left|200px]]
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caption="1clu, resolution 1.7&Aring;" />
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'''H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP'''<br />
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{{Structure
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|PDB= 1clu |SIZE=350|CAPTION= <scene name='initialview01'>1clu</scene>, resolution 1.7&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> and <scene name='pdbligand=DBG:3-AMINOBENZOPHENONE-4-YL-AMINOHYDROXYPHOSPHINYLAMINOPHOSPHONIC ACID-GUANYLATE ESTER'>DBG</scene>
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|ACTIVITY=
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|GENE= H-RAS-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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}}
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'''H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1CLU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=DBG:'>DBG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CLU OCA].
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1CLU 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=1CLU OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10359839 10359839]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/10359839 10359839]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: signal transduction]]
[[Category: signal transduction]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:07:21 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:25:57 2008''

Revision as of 08:25, 20 March 2008

Image:1clu.gif


PDB ID 1clu

Drag the structure with the mouse to rotate
, resolution 1.7Å
Ligands: and
Gene: H-RAS-1 (Homo sapiens)
Coordinates: save as pdb, mmCIF, xml



H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP


Contents

Overview

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.

Disease

Known diseases associated with this structure: Bladder cancer, somatic OMIM:[190020], Costello syndrome OMIM:[190020], Thyroid carcinoma, follicular, somatic OMIM:[190020]

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

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