Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism.

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ID: 97532
2020
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Abstract
By analyzing and simulating inactive conformations of the highly-homologous dopamine D and D receptors (DR and DR), we find that eticlopride binds DR in a pose very similar to that in the DR/eticlopride structure but incompatible with the DR/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 DR/risperidone structure to an extended conformation similar to that in the DR/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of DR. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.
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lane2020distinctelife Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Lane, J Robert;Abramyan, Ara M;Adhikari, Pramisha;Keen, Alastair C;Lee, Kuo-Hao;Sanchez, Julie;Verma, Ravi Kumar;Lim, Herman D;Yano, Hideaki;Javitch, Jonathan A;Shi, Lei;
Journal eLife
Year 2020
DOI
10.7554/eLife.52189
URL
Keywords
none biochemistry molecular biophysics structural biology chemical biology

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