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

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

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.

Citation

Lane, J. R., Abramyan, A. M., Adhikari, P., Keen, A. C., Lee, K.-H., Sanchez, J., Verma, R. K., Lim, H. D., Yano, H., Javitch, J. A., & Shi, L. (2020). Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism. eLife, 9, Article e52189. https://doi.org/10.7554/elife.52189

• Journal Article Type: Article
• Acceptance Date: Jan 24, 2020
• Online Publication Date: Jan 27, 2020
• Publication Date: Jan 27, 2020
• Deposit Date: Feb 27, 2020
• Publicly Available Date: Feb 27, 2020
• Journal: eLife
• Electronic ISSN: 2050-084X
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: e52189
• DOI: https://doi.org/10.7554/elife.52189
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Immunology and Microbiology; General Neuroscience; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4046260
• Publisher URL: https://elifesciences.org/articles/52189