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Structural basis for activation of CB1 by an endocannabinoid analog
Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implicat...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10169858/ https://www.ncbi.nlm.nih.gov/pubmed/37160876 http://dx.doi.org/10.1038/s41467-023-37864-4 |
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author | Krishna Kumar, Kaavya Robertson, Michael J. Thadhani, Elina Wang, Haoqing Suomivuori, Carl-Mikael Powers, Alexander S. Ji, Lipin Nikas, Spyros P. Dror, Ron O. Inoue, Asuka Makriyannis, Alexandros Skiniotis, Georgios Kobilka, Brian |
author_facet | Krishna Kumar, Kaavya Robertson, Michael J. Thadhani, Elina Wang, Haoqing Suomivuori, Carl-Mikael Powers, Alexander S. Ji, Lipin Nikas, Spyros P. Dror, Ron O. Inoue, Asuka Makriyannis, Alexandros Skiniotis, Georgios Kobilka, Brian |
author_sort | Krishna Kumar, Kaavya |
collection | PubMed |
description | Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the “toggle switch” residues F200(3.36) and W356(6.48). Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator. |
format | Online Article Text |
id | pubmed-10169858 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101698582023-05-11 Structural basis for activation of CB1 by an endocannabinoid analog Krishna Kumar, Kaavya Robertson, Michael J. Thadhani, Elina Wang, Haoqing Suomivuori, Carl-Mikael Powers, Alexander S. Ji, Lipin Nikas, Spyros P. Dror, Ron O. Inoue, Asuka Makriyannis, Alexandros Skiniotis, Georgios Kobilka, Brian Nat Commun Article Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the “toggle switch” residues F200(3.36) and W356(6.48). Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator. Nature Publishing Group UK 2023-05-09 /pmc/articles/PMC10169858/ /pubmed/37160876 http://dx.doi.org/10.1038/s41467-023-37864-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Krishna Kumar, Kaavya Robertson, Michael J. Thadhani, Elina Wang, Haoqing Suomivuori, Carl-Mikael Powers, Alexander S. Ji, Lipin Nikas, Spyros P. Dror, Ron O. Inoue, Asuka Makriyannis, Alexandros Skiniotis, Georgios Kobilka, Brian Structural basis for activation of CB1 by an endocannabinoid analog |
title | Structural basis for activation of CB1 by an endocannabinoid analog |
title_full | Structural basis for activation of CB1 by an endocannabinoid analog |
title_fullStr | Structural basis for activation of CB1 by an endocannabinoid analog |
title_full_unstemmed | Structural basis for activation of CB1 by an endocannabinoid analog |
title_short | Structural basis for activation of CB1 by an endocannabinoid analog |
title_sort | structural basis for activation of cb1 by an endocannabinoid analog |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10169858/ https://www.ncbi.nlm.nih.gov/pubmed/37160876 http://dx.doi.org/10.1038/s41467-023-37864-4 |
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