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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Fay, Jonathan F. Farrens, David L. |
| Description | Author Affiliation: Fay JF ( Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239-3098.); Farrens DL ( Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239-3098 farrensd@ohsu.edu.); |
| Abstract | G protein-coupled receptors (GPCRs) are surprisingly flexible molecules that can do much more than simply turn on G proteins. Some even exhibit biased signaling, wherein the same receptor preferentially activates different G-protein or arrestin signaling pathways depending on the type of ligand bound. Why this behavior occurs is still unclear, but it can happen with both traditional ligands and ligands that bind allosterically outside the orthosteric receptor binding pocket. Here, we looked for structural mechanisms underlying these phenomena in the marijuana receptor $CB_{1}.$ Our work focused on the allosteric ligand Org 27569, which has an unusual effect on $CB_{1}—it$ simultaneously increases agonist binding, decreases G-protein activation, and induces biased signaling. Using classical pharmacological binding studies, we find that Org 27569 binds to a unique allosteric site on $CB_{1}$ and show that it can act alone (without need for agonist cobinding). Through mutagenesis studies, we find that the ability of Org 27569 to bind is related to how much receptor is in an active conformation that can couple with G protein. Using these data, we estimated the energy differences between the inactive and active states. Finally, site-directed fluorescence labeling studies show the $CB_{1}$ structure stabilized by Org 27569 is different and unique from that stabilized by antagonist or agonist. Specifically, transmembrane helix 6 (TM6) movements associated with G-protein activation are blocked, but at the same time, helix 8/TM7 movements are enhanced, suggesting a possible mechanism for the ability of Org 27569 to induce biased signaling. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 27 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cannabinoid Receptor Agonists Metabolism Cannabinoid Receptor Antagonists Receptor, Cannabinoid, CB1 Chemistry Algorithms Animals Binding, Competitive COS Cells Cercopithecus Aethiops Cyclohexanols Guanosine 5'-O-(3-Thiotriphosphate) Indoles Kinetics Models, Biological Models, Molecular Mutation Piperidines Protein Conformation Protein Structure, Secondary Protein Structure, Tertiary Pyrazoles Radioligand Assay Genetics Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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