Structural basis of THC analog activity at the Cannabinoid 1 receptor
Abstract Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we dete...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55808-4 |
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| author | Thor S. Thorsen Yashraj Kulkarni David A. Sykes Andreas Bøggild Taner Drace Pattarin Hompluem Christos Iliopoulos-Tsoutsouvas Spyros P. Nikas Henrik Daver Alexandros Makriyannis Poul Nissen Michael Gajhede Dmitry B. Veprintsev Thomas Boesen Jette S. Kastrup David E. Gloriam |
| author_facet | Thor S. Thorsen Yashraj Kulkarni David A. Sykes Andreas Bøggild Taner Drace Pattarin Hompluem Christos Iliopoulos-Tsoutsouvas Spyros P. Nikas Henrik Daver Alexandros Makriyannis Poul Nissen Michael Gajhede Dmitry B. Veprintsev Thomas Boesen Jette S. Kastrup David E. Gloriam |
| author_sort | Thor S. Thorsen |
| collection | DOAJ |
| description | Abstract Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines. |
| format | Article |
| id | doaj-art-626bd222e009428aaf026567f1c58af3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-626bd222e009428aaf026567f1c58af32025-01-12T12:30:15ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-024-55808-4Structural basis of THC analog activity at the Cannabinoid 1 receptorThor S. Thorsen0Yashraj Kulkarni1David A. Sykes2Andreas Bøggild3Taner Drace4Pattarin Hompluem5Christos Iliopoulos-Tsoutsouvas6Spyros P. Nikas7Henrik Daver8Alexandros Makriyannis9Poul Nissen10Michael Gajhede11Dmitry B. Veprintsev12Thomas Boesen13Jette S. Kastrup14David E. Gloriam15Department of Drug Design and Pharmacology, University of CopenhagenDepartment of Drug Design and Pharmacology, University of CopenhagenCentre of Membrane Proteins and Receptors (COMPARE), University of NottinghamInterdisciplinary Nanoscience Center and Department of Molecular Biology & Genetics, Aarhus UniversityInterdisciplinary Nanoscience Center and Department of Molecular Biology & Genetics, Aarhus UniversityCentre of Membrane Proteins and Receptors (COMPARE), University of NottinghamCenter for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern UniversityCenter for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern UniversityDepartment of Drug Design and Pharmacology, University of CopenhagenCenter for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern UniversityInterdisciplinary Nanoscience Center and Department of Molecular Biology & Genetics, Aarhus UniversityDepartment of Drug Design and Pharmacology, University of CopenhagenCentre of Membrane Proteins and Receptors (COMPARE), University of NottinghamInterdisciplinary Nanoscience Center and Department of Molecular Biology & Genetics, Aarhus UniversityDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Drug Design and Pharmacology, University of CopenhagenAbstract Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.https://doi.org/10.1038/s41467-024-55808-4 |
| spellingShingle | Thor S. Thorsen Yashraj Kulkarni David A. Sykes Andreas Bøggild Taner Drace Pattarin Hompluem Christos Iliopoulos-Tsoutsouvas Spyros P. Nikas Henrik Daver Alexandros Makriyannis Poul Nissen Michael Gajhede Dmitry B. Veprintsev Thomas Boesen Jette S. Kastrup David E. Gloriam Structural basis of THC analog activity at the Cannabinoid 1 receptor Nature Communications |
| title | Structural basis of THC analog activity at the Cannabinoid 1 receptor |
| title_full | Structural basis of THC analog activity at the Cannabinoid 1 receptor |
| title_fullStr | Structural basis of THC analog activity at the Cannabinoid 1 receptor |
| title_full_unstemmed | Structural basis of THC analog activity at the Cannabinoid 1 receptor |
| title_short | Structural basis of THC analog activity at the Cannabinoid 1 receptor |
| title_sort | structural basis of thc analog activity at the cannabinoid 1 receptor |
| url | https://doi.org/10.1038/s41467-024-55808-4 |
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