Abstract:
:Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β2 adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics (MD) simulations. These reveal shifts towards active-like states at the G protein binding site for receptors bound to partial and full agonists and that the ligands modulate the conformational ensemble of the receptor by tuning protein microswitches. We indeed find an excellent correlation between the conformation of the microswitches close to the ligand binding site and in the transmembrane region and experimentally reported cAMP signaling responses. Dimensionality reduction further reveals the similarity between the unique conformational states induced by different ligands and examining the output of classifiers highlights two distant hotspots governing agonism on transmembrane helices 5 and 7.
journal_name
Elifejournal_title
eLifeauthors
Fleetwood O,Carlsson J,Delemotte Ldoi
10.7554/eLife.60715subject
Has Abstractpub_date
2021-01-28 00:00:00issn
2050-084Xpii
60715journal_volume
10pub_type
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