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Nature communications
Oct 19, 2024;15 (1): 9040.

A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1.

Alessio Bartocci, Andrea Grazzi, Nour Awad, Pierre-Jean Corringer, Paulo C T Souza, Marco Cecchini
Author Information
  1. Alessio Bartocci: Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg, Strasbourg Cedex, 67083, France. ORCID
  2. Andrea Grazzi: Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg, Strasbourg Cedex, 67083, France. ORCID
  3. Nour Awad: Institut Pasteur, Université de Paris, CNRS UMR3571, Channel-Receptors Unit, Paris, France.
  4. Pierre-Jean Corringer: Institut Pasteur, Université de Paris, CNRS UMR3571, Channel-Receptors Unit, Paris, France.
  5. Paulo C T Souza: Laboratoire de Biologie et Modélisation de la Cellule, CNRS, UMR 5239, Inserm, U1293, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364, Lyon, France. ORCID
  6. Marco Cecchini: Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg, Strasbourg Cedex, 67083, France. mcecchini@unistra.fr. ORCID
PMID: 39426952 DOI: 10.1038/s41467-024-53098-4

Abstract

Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate the GlyR response but their mechanism of action is not fully established. By combining millisecond coarse-grained (CG) MD simulations powered by Martini 3 with backmapping to all-atom representations, we have characterized the cannabinoid-binding site(s) at the zebrafish GlyR-α1 active state with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the ligand-receptor interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA have been validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and put forward an effective strategy for the identification and structural characterization of allosteric binding sites.

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Grants

  1. ANR-18- CE11-0015/Agence Nationale de la Recherche (French National Research Agency)
  2. 956314 (ALLODD)/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)
  3. 788974 (Dynacotine)/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)

MeSH Term

Animals
Molecular Dynamics Simulation
Receptors, Glycine
Zebrafish
Allosteric Site
Binding Sites
Arachidonic Acids
Dronabinol
Allosteric Regulation
Cannabinoids
Protein Binding
Polyunsaturated Alkamides
Endocannabinoids
Ligands
Cryoelectron Microscopy

Chemicals

Receptors, Glycine
Arachidonic Acids
Dronabinol
Cannabinoids
Polyunsaturated Alkamides
Endocannabinoids
anandamide
Ligands
Journal Article
Article has an altmetric score of 9

Word Cloud

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