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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Rudack, Till Schlitter, Jürgen Xia, Fei Gerwert, Klaus Kötting, Carsten |
| Description | Author Affiliation: Rudack T ( Department of Biophysics, Ruhr-University Bochum, Bochum, Germany.); |
| Abstract | Members of the Ras superfamily regulate many cellular processes. They are down-regulated by a GTPase reaction in which GTP is cleaved into GDP and P(i) by nucleophilic attack of a water molecule. Ras proteins accelerate GTP hydrolysis by a factor of 10(5) compared to GTP in water. GTPase-activating proteins (GAPs) accelerate hydrolysis by another factor of 10(5) compared to Ras alone. Oncogenic mutations in Ras and GAPs slow GTP hydrolysis and are a factor in many cancers. Here, we elucidate in detail how this remarkable catalysis is brought about. We refined the protein-bound GTP structure and protein-induced charge shifts within GTP beyond the current resolution of X-ray structural models by combining quantum mechanics and molecular mechanics simulations with time-resolved Fourier-transform infrared spectroscopy. The simulations were validated by comparing experimental and theoretical IR difference spectra. The reactant structure of GTP is destabilized by Ras via a conformational change from a staggered to an eclipsed position of the nonbridging oxygen atoms of the γ- relative to the ß-phosphates and the further rotation of the nonbridging oxygen atoms of - relative to the ß- and γ-phosphates by GAP. Further, the γ-phosphate becomes more positive although two of its oxygen atoms remain negative. This facilitates the nucleophilic attack by the water oxygen at the phosphate and proton transfer to the oxygen. Detailed changes in geometry and charge distribution in the ligand below the resolution of X-ray structure analysis are important for catalysis. Such high resolution appears crucial for the understanding of enzyme catalysis. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | GTPase-Activating Proteins Genetics Metabolism Guanosine Triphosphate Chemistry Spectroscopy, Fourier Transform Infrared Catalysis Computer Simulation Hydrolysis Ligands Magnesium Molecular Conformation Molecular Dynamics Simulation Oxygen Phosphates Protein Conformation Protons Spectrophotometry, Infrared Thermodynamics X-Rays Ras Proteins Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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