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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. / Gregorio, G. Glenn; Masureel, Matthieu; Hilger, Daniel; Terry, Daniel S.; Juette, Manuel; Zhao, Hong; Zhou, Zhou; Perez-Aguilar, Jose Manuel; Hauge, Maria; Mathiasen, Signe; Javitch, Jonathan A.; Weinstein, Harel; Kobilka, Brian K.; Blanchard, Scott C.

In: Nature, Vol. 547, No. 7661, 2017, p. 68–73.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Gregorio, GG, Masureel, M, Hilger, D, Terry, DS, Juette, M, Zhao, H, Zhou, Z, Perez-Aguilar, JM, Hauge, M, Mathiasen, S, Javitch, JA, Weinstein, H, Kobilka, BK & Blanchard, SC 2017, 'Single-molecule analysis of ligand efficacy in β2AR-G-protein activation', Nature, vol. 547, no. 7661, pp. 68–73. https://doi.org/10.1038/nature22354

APA

Gregorio, G. G., Masureel, M., Hilger, D., Terry, D. S., Juette, M., Zhao, H., Zhou, Z., Perez-Aguilar, J. M., Hauge, M., Mathiasen, S., Javitch, J. A., Weinstein, H., Kobilka, B. K., & Blanchard, S. C. (2017). Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. Nature, 547(7661), 68–73. https://doi.org/10.1038/nature22354

Vancouver

Gregorio GG, Masureel M, Hilger D, Terry DS, Juette M, Zhao H et al. Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. Nature. 2017;547(7661):68–73. https://doi.org/10.1038/nature22354

Author

Gregorio, G. Glenn ; Masureel, Matthieu ; Hilger, Daniel ; Terry, Daniel S. ; Juette, Manuel ; Zhao, Hong ; Zhou, Zhou ; Perez-Aguilar, Jose Manuel ; Hauge, Maria ; Mathiasen, Signe ; Javitch, Jonathan A. ; Weinstein, Harel ; Kobilka, Brian K. ; Blanchard, Scott C. / Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. In: Nature. 2017 ; Vol. 547, No. 7661. pp. 68–73.

Bibtex

@article{c2035450f453446fb292b54db0ba513f,
title = "Single-molecule analysis of ligand efficacy in β2AR-G-protein activation",
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.",
author = "Gregorio, {G. Glenn} and Matthieu Masureel and Daniel Hilger and Terry, {Daniel S.} and Manuel Juette and Hong Zhao and Zhou Zhou and Perez-Aguilar, {Jose Manuel} and Maria Hauge and Signe Mathiasen and Javitch, {Jonathan A.} and Harel Weinstein and Kobilka, {Brian K.} and Blanchard, {Scott C.}",
year = "2017",
doi = "10.1038/nature22354",
language = "English",
volume = "547",
pages = "68–73",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",
number = "7661",

}

RIS

TY - JOUR

T1 - Single-molecule analysis of ligand efficacy in β2AR-G-protein activation

AU - Gregorio, G. Glenn

AU - Masureel, Matthieu

AU - Hilger, Daniel

AU - Terry, Daniel S.

AU - Juette, Manuel

AU - Zhao, Hong

AU - Zhou, Zhou

AU - Perez-Aguilar, Jose Manuel

AU - Hauge, Maria

AU - Mathiasen, Signe

AU - Javitch, Jonathan A.

AU - Weinstein, Harel

AU - Kobilka, Brian K.

AU - Blanchard, Scott C.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/nature22354

DO - 10.1038/nature22354

M3 - Journal article

C2 - 28607487

VL - 547

SP - 68

EP - 73

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7661

ER -

ID: 182486194