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.
Highlights
G Protein-Coupled Receptors (GPCRs) are membrane proteins that transduce the signals of hormones, neurotransmitters and metabolites into an appropriate cellular response [1]
The use of free energy calculation methods has arisen as a computational tool to predict ligand affinities to explain structure-affinity relationships and guide lead optimization campaigns
We report an original implementation of the thermodynamic cycles associated with free energy perturbation
Summary
G Protein-Coupled Receptors (GPCRs) are membrane proteins that transduce the signals of hormones, neurotransmitters and metabolites into an appropriate cellular response [1]. The structures of ternary GPCR complexes, including the intracellular signalling G proteins or β-arrestin in addition to an orthosteric agonist, were resolved in recent years mainly due to advances in cryo-EM [7,8]. GPCR activation has been described as a two-state model, where the receptor would transition from an inactive (R) to an active (R ) conformation (Fig 1A) [9]. This relatively simplistic model becomes more realistic when considering the influence on the receptor equilibrium of chemical modulators (Fig 1B), receptor mutations (Fig 1C) or even the intracellular signalling protein [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
