ArticleProceedings of the National Academy of Sciences of the United States of America2015
Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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Who cites it
29 citing papers in PubMed, 48 citations in OpenAlex.
- Article
- How Ligands Achieve Biased Signaling toward Arrestins.Biochemistry · 2025Review
- Insight into the mechanism of action of ORG27569 at the cannabinoid type one receptor utilising a unified mathematical model.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Insights on the G protein-coupled receptor helix 8 solution structure and orientation using a neurotensin receptor 1 peptide.Protein science : a publication of the Protein Society · 2024Article
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- The NPXXY Motif Regulates β-Arrestin Recruitment by the CB1 Cannabinoid Receptor.Cannabis and cannabinoid research · 2023Article
- Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery.Nature communications · 2023Article
- Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34.British journal of pharmacology · 2022Review
- Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593.Frontiers in pharmacology · 2022Article
- CB1 Cannabinoid Receptor Signaling and Biased Signaling.Molecules (Basel, Switzerland) · 2021Review
- Hemopressin as a breakthrough for the cannabinoid field.Neuropharmacology · 2021Review
- Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations.The Journal of biological chemistry · 2020Article
- Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.Trends in cell biology · 2020Review
- The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CBInternational journal of molecular sciences · 2020Article
- Conformational dynamics of a G protein-coupled receptor helix 8 in lipid membranes.Science advances · 2020Article
- Molecular Mechanism and Cannabinoid Pharmacology.Handbook of experimental pharmacology · 2020Article
- Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.Nature chemical biology · 2019Article
- Selective modulation of the cannabinoid type 1 (CBMedChemComm · 2019Review
- Structural Insights into CB1 Receptor Biased Signaling.International journal of molecular sciences · 2019Review
- Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
G protein-coupled receptors (GPCRs) are surprisingly flexible molecules that can do much more than simply turn on G proteins. Some even exhibit biased signaling, wherein the same receptor preferentially activates different G-protein or arrestin signaling pathways depending on the type of ligand bound. Why this behavior occurs is still unclear, but it can happen with both traditional ligands and ligands that bind allosterically outside the orthosteric receptor binding pocket. Here, we looked for structural mechanisms underlying these phenomena in the marijuana receptor CB1. Our work focused on the allosteric ligand Org 27569, which has an unusual effect on CB1-it simultaneously increases agonist binding, decreases G--protein activation, and induces biased signaling. Using classical pharmacological binding studies, we find that Org 27569 binds to a unique allosteric site on CB1 and show that it can act alone (without need for agonist cobinding). Through mutagenesis studies, we find that the ability of Org 27569 to bind is related to how much receptor is in an active conformation that can couple with G protein. Using these data, we estimated the energy differences between the inactive and active states. Finally, site-directed fluorescence labeling studies show the CB1 structure stabilized by Org 27569 is different and unique from that stabilized by antagonist or agonist. Specifically, transmembrane helix 6 (TM6) movements associated with G-protein activation are blocked, but at the same time, helix 8/TM7 movements are enhanced, suggesting a possible mechanism for the ability of Org 27569 to induce biased signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.