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., Sanchez, J., …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