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Guanosine triphosphatase stimulation of oncogenic Ras mutants

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons98673

Ahmadian,  Mohammad Reza
Sonstige Wissenschaftliche Organisationseinheiten, Max Planck Institute of Molecular Physiology, Max Planck Society;

Vogt,  Dorothee
Max Planck Institute of Molecular Physiology, Max Planck Society;

Kabsch,  Wolfgang
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98738

Wittinghofer,  Alfred
Sonstige Wissenschaftliche Organisationseinheiten, Max Planck Institute of Molecular Physiology, Max Planck Society;

Scheffzek,  Klaus
Max Planck Institute of Molecular Physiology, Max Planck Society;

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Citation

Ahmadian, M. R., Zor, T., Vogt, D., Kabsch, W., Selinger, Z., Wittinghofer, A., et al. (1999). Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proceedings of the National Academy of Sciences of the United States of America, 96(12): 1, pp. 7065-7070. Retrieved from http://www.pnas.org/cgi/reprint/96/12/7065.pdf.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-1044-1
Abstract
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 (CTP) analogue diaminobenzophenone-phosphoroamidate-GTP (DABP-GTP) is hydrolyzed by wildtype 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 GTPas