Academic Journal
Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
| العنوان: | Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism |
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| المؤلفون: | J Robert Lane, Ara M Abramyan, Pramisha Adhikari, Alastair C Keen, Kuo-Hao Lee, Julie Sanchez, Ravi Kumar Verma, Herman D Lim, Hideaki Yano, Jonathan A Javitch, Lei Shi |
| المصدر: | eLife, Vol 9 (2020) |
| بيانات النشر: | eLife Sciences Publications Ltd, 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Medicine LCC:Science LCC:Biology (General) |
| مصطلحات موضوعية: | dopamine d2 receptor, na+ sensitivity, inverse agonism, molecular dynamics, Medicine, Science, Biology (General), QH301-705.5 |
| الوصف: | By analyzing and simulating inactive conformations of the highly homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2050-084X |
| Relation: | https://elifesciences.org/articles/52189; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.52189 |
| URL الوصول: | https://doaj.org/article/22ae5702392642ec91760a357236acbd |
| رقم الانضمام: | edsdoj.22ae5702392642ec91760a357236acbd |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.52189 |