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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Dror, Ron O. Villanueva, Nicolas Hilger, Daniel Yang, Zhongyu Hubbell, Wayne L. Manglik, Aashish Kobilka, Brian K. Sunahara, Roger K. Shaw, David E. Arlow, Daniel H. Borhani, David W. Philippsen, Ansgar Mildorf, Thomas J. Lerch, Michael T. |
| Description | Author Affiliation: Dror RO ( D. E. Shaw Research, New York, NY 10036, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.); Mildorf TJ ( D. E. Shaw Research, New York, NY 10036, USA.); Hilger D ( Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.); Manglik A ( Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.); Borhani DW ( D. E. Shaw Research, New York, NY 10036, USA.); Arlow DH ( D. E. Shaw Research, New York, NY 10036, USA.); Philippsen A ( D. E. Shaw Research, New York, NY 10036, USA.); Villanueva N ( Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.); Yang Z ( Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.); Lerch MT ( Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.); Hubbell WL ( Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.); Kobilka BK ( Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.); Sunahara RK ( Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.); Shaw DE ( D. E. Shaw Research, New York, NY 10036, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.) |
| Abstract | G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism. |
| ISSN | 00368075 |
| e-ISSN | 10959203 |
| Journal | Science |
| Issue Number | 6241 |
| Volume Number | 348 |
| Language | English |
| Publisher | American Association for the Advancement of Science (United States) |
| Publisher Date | 2015-06-19 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | GTP-Binding Protein Alpha Subunits, Gi-Go Chemistry GTP-Binding Protein Alpha Subunits, Gs Guanine Nucleotide Exchange Factors Receptors, G-Protein-Coupled Models, Chemical Molecular Dynamics Simulation Protein Structure, Secondary Protein Structure, Tertiary Signal Transduction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | History and Philosophy of Science |
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