ArticlePLoS computational biology2021
Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by free energy simulations.
Article in PLoS computational biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- Cancer-Associated Mutations of the Adenosine AMolecules (Basel, Switzerland) · 2022Article
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Authors and funding
7 authors.
Funding
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Abstract
Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A2AAR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.
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