ArticleThe Journal of biological chemistry2010
A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.
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Who cites it
109 citing papers in PubMed.
- Structural mechanisms underlying distinct binding and activities of 18:0 and 18:1 lysophosphatidic acids at LPA1 receptor.PLoS computational biology · 2026Article
- How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1.iScience · 2025Article
- Comparison of Agonist Activity between CB1 and CB2 Receptors with Orthosteric Site Mutations.Receptors (Basel, Switzerland) · 2024Article
- Structural and functional insights into the G protein-coupled receptors: CB1 and CB2.Biochemical Society transactions · 2023Review
- Novel Cannabinoid Receptor 2 (CB2) Low Lipophilicity Agonists Produce Distinct cAMP and Arrestin Signalling Kinetics without Bias.International journal of molecular sciences · 2023Article
- Special issue for Klaus Gawrisch.Biophysical journal · 2023Article
- Article
- A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CBJournal of chemical information and modeling · 2022Article
- Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of Cannabinoid CB1 Receptor Bound to a Negative Allosteric Modulator, ORG27569, and Analogs.Journal of medicinal chemistry · 2022Article
- Inhibition of NMDA receptors through a membrane-to-channel path.Nature communications · 2022Article
- Phospholipid Scrambling by G Protein-Coupled Receptors.Annual review of biophysics · 2022Review
- Interaction With the Lipid Membrane Influences Fentanyl Pharmacology.Advances in drug and alcohol research · 2022Article
- Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-ActingMolecular pharmacology · 2021Article
- Cannabinoids and Cannabinoid Receptors: The Story so Far.iScience · 2020Review
- Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor.ACS chemical neuroscience · 2020Article
- Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18.Biomolecules · 2020Article
- Lipid-Protein Interactions Are a Unique Property and Defining Feature of G Protein-Coupled Receptors.Biophysical journal · 2020Article
- GPR6 Structural Insights: Homology Model Construction and Docking Studies.Molecules (Basel, Switzerland) · 2020Article
49 more citing papers are in PubMed but not listed here.
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8 authors.
Funding
Abstract
Recent isothiocyanate covalent labeling studies have suggested that a classical cannabinoid, (-)-7'-isothiocyanato-11-hydroxy-1',1'dimethylheptyl-hexahydrocannabinol (AM841), enters the cannabinoid CB2 receptor via the lipid bilayer (Pei, Y., Mercier, R. W., Anday, J. K., Thakur, G. A., Zvonok, A. M., Hurst, D., Reggio, P. H., Janero, D. R., and Makriyannis, A. (2008) Chem. Biol. 15, 1207-1219). However, the sequence of steps involved in such a lipid pathway entry has not yet been elucidated. Here, we test the hypothesis that the endogenous cannabinoid sn-2-arachidonoylglycerol (2-AG) attains access to the CB2 receptor via the lipid bilayer. To this end, we have employed microsecond time scale all-atom molecular dynamics (MD) simulations of the interaction of 2-AG with CB2 via a palmitoyl-oleoyl-phosphatidylcholine lipid bilayer. Results suggest the following: 1) 2-AG first partitions out of bulk lipid at the transmembrane alpha-helix (TMH) 6/7 interface; 2) 2-AG then enters the CB2 receptor binding pocket by passing between TMH6 and TMH7; 3) the entrance of the 2-AG headgroup into the CB2 binding pocket is sufficient to trigger breaking of the intracellular TMH3/6 ionic lock and the movement of the TMH6 intracellular end away from TMH3; and 4) subsequent to protonation at D3.49/D6.30, further 2-AG entry into the ligand binding pocket results in both a W6.48 toggle switch change and a large influx of water. To our knowledge, this is the first demonstration via unbiased molecular dynamics that a ligand can access the binding pocket of a class A G protein-coupled receptor via the lipid bilayer and the first demonstration via molecular dynamics of G protein-coupled receptor activation triggered by a ligand binding event.
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