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

Author

Listed:
  • 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
    IBM Thomas J. Watson Research Center, Yorktown Heights)

  • Maria Hauge

    (Columbia University College of Physicians and Surgeons
    New York State Psychiatric Institute
    Laboratory for Molecular Pharmacology, University of Copenhagen
    NNF Center for Basic Metabolic Research, University of Copenhagen)

  • Signe Mathiasen

    (Columbia University College of Physicians and Surgeons
    New York State Psychiatric Institute)

  • Jonathan A. Javitch

    (Columbia University College of Physicians and Surgeons
    New York State Psychiatric Institute
    Columbia University College of Physicians and Surgeons)

  • Harel Weinstein

    (Weill Cornell Medicine
    The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Scott C. Blanchard

    (Weill Cornell Medicine)

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.

Suggested Citation

  • 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 & Hare, 2017. "Single-molecule analysis of ligand efficacy in β2AR–G-protein activation," Nature, Nature, vol. 547(7661), pages 68-73, July.
  • Handle: RePEc:nat:nature:v:547:y:2017:i:7661:d:10.1038_nature22354
    DOI: 10.1038/nature22354
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    Cited by:

    1. Chris Habrian & Naomi Latorraca & Zhu Fu & Ehud Y. Isacoff, 2023. "Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Kaavya Krishna Kumar & Michael J. Robertson & Elina Thadhani & Haoqing Wang & Carl-Mikael Suomivuori & Alexander S. Powers & Lipin Ji & Spyros P. Nikas & Ron O. Dror & Asuka Inoue & Alexandros Makriya, 2023. "Structural basis for activation of CB1 by an endocannabinoid analog," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Jie Heng & Yunfei Hu & Guillermo Pérez-Hernández & Asuka Inoue & Jiawei Zhao & Xiuyan Ma & Xiaoou Sun & Kouki Kawakami & Tatsuya Ikuta & Jienv Ding & Yujie Yang & Lujia Zhang & Sijia Peng & Xiaogang N, 2023. "Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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