Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
- University of Nottingham, United Kingdom
- National Institute on Drug Abuse, National Institutes of Health, United States
- Monash University, Australia
- Columbia University, United States
Abstract
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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (Z1A DA000606-03)
- Lei Shi
National Institutes of Health (MH54137)
- Jonathan A Javitch
National Health and Medical Research Council (APP1049564)
- J Robert Lane
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
eLife 9:e52189.
https://doi.org/10.7554/eLife.52189
