Single-molecule analysis of ligand efficacy in β2AR–G-protein activation

G. Glenn Gregorio, Matthieu Masureel, Daniel Hilger, Daniel S. Terry, Manuel Juette, Hong Zhao, Zhou Zhou, Jose Manuel Perez-Aguilar, Maria Hauge, Signe Mathiasen, Jonathan A. Javitch, Harel Weinstein, Brian K. Kobilka () and Scott C. Blanchard ()
Additional contact information
G. Glenn Gregorio: Weill Cornell Medicine
Matthieu Masureel: Stanford University School of Medicine
Daniel Hilger: Stanford University School of Medicine
Daniel S. Terry: Weill Cornell Medicine
Manuel Juette: Weill Cornell Medicine
Hong Zhao: Weill Cornell Medicine
Zhou Zhou: Weill Cornell Medicine
Jose Manuel Perez-Aguilar: Weill Cornell Medicine
Maria Hauge: Columbia University College of Physicians and Surgeons
Signe Mathiasen: Columbia University College of Physicians and Surgeons
Jonathan A. Javitch: Columbia University College of Physicians and Surgeons
Harel Weinstein: Weill Cornell Medicine
Brian K. Kobilka: Stanford University School of Medicine
Scott C. Blanchard: Weill Cornell Medicine

Nature, 2017, vol. 547, issue 7661, 68-73

Abstract: Abstract G-protein-coupled receptor (GPCR)-mediated signal transduction is central to human physiology and disease intervention, yet the molecular mechanisms responsible for ligand-dependent signalling responses remain poorly understood. In class A GPCRs, receptor activation and G-protein coupling entail outward movements of transmembrane helix 6 (TM6). Here, using single-molecule fluorescence resonance energy transfer imaging, we examine TM6 movements in the β2 adrenergic receptor (β2AR) upon exposure to orthosteric ligands with different efficacies, in the absence and presence of the Gs heterotrimer. We show that partial and full agonists differentially affect TM6 motions to regulate the rate at which GDP-bound β2AR–Gs complexes are formed and the efficiency of nucleotide exchange leading to Gs activation. These data also reveal transient nucleotide-bound β2AR–Gs species that are distinct from known structures, and provide single-molecule perspectives on the allosteric link between ligand- and nucleotide-binding pockets that shed new light on the G-protein activation mechanism.

Date: 2017
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DOI: 10.1038/nature22354

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