Guanosine triphosphatase stimulation of oncogenic Ras mutants

摘要: Interest in the guanosine triphosphatase (GTPase) reaction of Ras as a molecular drug target stems from observation that, large number human tumors, is characteristically mutated at codons 12 or 61, more rarely 13. Impaired GTPase activity, even presence activating proteins, has been found to be biochemical reason behind oncogenicity most Gly12/Gln61 mutations, thus preventing being switched off. Therefore, these oncogenic mutants remain constitutively activated and contribute neoplastic phenotype tumor cells. Here, we show that 5′-triphosphate (GTP) analogue diaminobenzophenone-phosphoroamidate-GTP (DABP-GTP) hydrolyzed by wild-type but efficiently frequently occurring mutants, yield 5′-diphosphate-bound inactive DABP-Pi. The independent Gln61 dramatically enhanced with Gly12 mutants. Thus, defective can rescued using DABP-GTP instead GTP, arguing switch not irreversibly damaged. An exocyclic aromatic amino group critical for bypasses putative rate-limiting step intrinsic reaction. crystal structures Ras-bound DABP-β,γ-imido-GTP disordered I identify Gly12/Gly13 region hydrophobic patch accommodate DABP-moiety. structural studies help define requirements design anti-Ras drugs aimed blocked