Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation

Abstract The cannabinoid receptor 1 (CB1) is a class A G-protein coupled receptor (GPCR) that can exert various effects on the human body through the endocannabinoid system. Understanding CB1 activation has many benefits for the medical use of cannabinoids. A previous study reported that CB1 has two...

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Autores principales:	Sangho Ji, Wonjin Yang, Wookyung Yu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49b2ba77c8c6412a9b5a4f1df9eaee40
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spelling	oai:doaj.org-article:49b2ba77c8c6412a9b5a4f1df9eaee402021-11-21T12:24:48ZUnderstanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation10.1038/s41598-021-01767-52045-2322https://doaj.org/article/49b2ba77c8c6412a9b5a4f1df9eaee402021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01767-5https://doaj.org/toc/2045-2322Abstract The cannabinoid receptor 1 (CB1) is a class A G-protein coupled receptor (GPCR) that can exert various effects on the human body through the endocannabinoid system. Understanding CB1 activation has many benefits for the medical use of cannabinoids. A previous study reported that CB1 has two notable residues referred to as the toggle switch, F3.36 and W6.48, which are important for its activation mechanism. We performed a molecular dynamics simulation with a mutation in the toggle switch to examine its role in active and inactive states. We also examined structural changes, the residue–residue interaction network, and the interaction network among helices and loops of wildtype and mutant CB1 for both activation states. As a result, we found that the energetic changes in the hydrogen-bond network of the Na+ pocket, extracellular N-terminus–TM2–ECL1–TM3 interface including D2.63–K3.28 salt-bridge, and extracellular ECL2–TM5–ECL3–TM6 interface directly linked to the toggle switch contribute to the stability of CB1 by the broken aromatic interaction of the toggle switch. It makes the conformation of inactive CB1 receptor to be unstable. Our study explained the role of the toggle switch regarding the energetic interactions related to the Na+ pocket and extracellular loop interfaces, which could contribute to a better understanding of the activation mechanism of CB1.Sangho JiWonjin YangWookyung YuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sangho Ji Wonjin Yang Wookyung Yu Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
description	Abstract The cannabinoid receptor 1 (CB1) is a class A G-protein coupled receptor (GPCR) that can exert various effects on the human body through the endocannabinoid system. Understanding CB1 activation has many benefits for the medical use of cannabinoids. A previous study reported that CB1 has two notable residues referred to as the toggle switch, F3.36 and W6.48, which are important for its activation mechanism. We performed a molecular dynamics simulation with a mutation in the toggle switch to examine its role in active and inactive states. We also examined structural changes, the residue–residue interaction network, and the interaction network among helices and loops of wildtype and mutant CB1 for both activation states. As a result, we found that the energetic changes in the hydrogen-bond network of the Na+ pocket, extracellular N-terminus–TM2–ECL1–TM3 interface including D2.63–K3.28 salt-bridge, and extracellular ECL2–TM5–ECL3–TM6 interface directly linked to the toggle switch contribute to the stability of CB1 by the broken aromatic interaction of the toggle switch. It makes the conformation of inactive CB1 receptor to be unstable. Our study explained the role of the toggle switch regarding the energetic interactions related to the Na+ pocket and extracellular loop interfaces, which could contribute to a better understanding of the activation mechanism of CB1.
format	article
author	Sangho Ji Wonjin Yang Wookyung Yu
author_facet	Sangho Ji Wonjin Yang Wookyung Yu
author_sort	Sangho Ji
title	Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
title_short	Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
title_full	Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
title_fullStr	Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
title_full_unstemmed	Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation
title_sort	understanding the role of the cb1 toggle switch in interaction networks using molecular dynamics simulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/49b2ba77c8c6412a9b5a4f1df9eaee40
work_keys_str_mv	AT sanghoji understandingtheroleofthecb1toggleswitchininteractionnetworksusingmoleculardynamicssimulation AT wonjinyang understandingtheroleofthecb1toggleswitchininteractionnetworksusingmoleculardynamicssimulation AT wookyungyu understandingtheroleofthecb1toggleswitchininteractionnetworksusingmoleculardynamicssimulation
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Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation

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