A 2A adenosine receptor functional states characterized by 19 F-NMR
| العنوان: | A 2A adenosine receptor functional states characterized by 19 F-NMR |
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| المؤلفون: | Raymond C. Stevens, Lukas Sušac, Tatiana Didenko, Kurt Wüthrich, Matthew T. Eddy |
| المصدر: | Proceedings of the National Academy of Sciences. 115:12733-12738 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Multidisciplinary, G protein, Chemistry, Allosteric regulation, Fluorine-19 NMR, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Drug Binding Site, Biophysics, Binding site, Receptor, Conformational ensembles, 030217 neurology & neurosurgery, G protein-coupled receptor |
| الوصف: | The human proteome contains 826 G protein-coupled receptors (GPCR), which control a wide array of key physiological functions, making them important drug targets. GPCR functions are based on allosteric coupling from the extracellular orthosteric drug binding site across the cell membrane to intracellular binding sites for partners such as G proteins and arrestins. This signaling process is related to dynamic equilibria in conformational ensembles that can be observed by NMR in solution. A previous high-resolution NMR study of the A2A adenosine receptor (A2AAR) resulted in a qualitative characterization of a network of such local polymorphisms. Here, we used 19F-NMR experiments with probes at the A2AAR intracellular surface, which provides the high sensitivity needed for a refined description of different receptor activation states by ensembles of simultaneously populated conformers and the rates of exchange among them. We observed two agonist-stabilized substates that are not measurably populated in apo-A2AAR and one inactive substate that is not seen in complexes with agonists, suggesting that A2AAR activation includes both induced fit and conformational selection mechanisms. Comparison of A2AAR and a constitutively active mutant established relations between the 19F-NMR spectra and signaling activity, which enabled direct assessment of the difference in basal activity between the native protein and its variant. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::caf6670fadf37565465d94e5a9cd6e1f https://doi.org/10.1073/pnas.1813649115 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........caf6670fadf37565465d94e5a9cd6e1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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