Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling

Fleetwood, Oliver, 1990- (author): KTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Stockholm, Sweden.

Carlsson, Jens (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för läkemedelskemi,Beräkningsbiologi och bioinformatik

Delemotte, Lucie (author): KTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Stockholm, Sweden.

(creator_code:org_t)

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Abstract Subject headings

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 beta(2) adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics simulations. These reveal shifts toward active-like states at the Gprotein-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 cyclic adenosine monophosphate 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.

By the author/editor: Fleetwood, Olive ...; Carlsson, Jens; Delemotte, Lucie

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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