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Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor

Author

Listed:
  • J. Niclas Frei

    (University of Cambridge)

  • Richard W. Broadhurst

    (University of Cambridge)

  • Mark J. Bostock

    (University of Cambridge
    Technical University of Munich)

  • Andras Solt

    (University of Cambridge)

  • Andrew J. Y. Jones

    (University of Cambridge)

  • Florian Gabriel

    (University of Cambridge)

  • Aditi Tandale

    (University of Cambridge)

  • Binesh Shrestha

    (Protein Sciences, CBT, Novartis Institutes for BioMedical Research (NIBR))

  • Daniel Nietlispach

    (University of Cambridge)

Abstract

G-protein-coupled receptors (GPCRs) are allosteric signaling proteins that transmit an extracellular stimulus across the cell membrane. Using 19F NMR and site-specific labelling, we investigate the response of the cytoplasmic region of transmembrane helices 6 and 7 of the β1-adrenergic receptor to agonist stimulation and coupling to a Gs-protein-mimetic nanobody. Agonist binding shows the receptor in equilibrium between two inactive states and a pre-active form, increasingly populated with higher ligand efficacy. Nanobody coupling leads to a fully active ternary receptor complex present in amounts correlating directly with agonist efficacy, consistent with partial agonism. While for different agonists the helix 6 environment in the active-state ternary complexes resides in a well-defined conformation, showing little conformational mobility, the environment of the highly conserved NPxxY motif on helix 7 remains dynamic adopting diverse, agonist-specific conformations, implying a further role of this region in receptor function. An inactive nanobody-coupled ternary receptor form is also observed.

Suggested Citation

  • J. Niclas Frei & Richard W. Broadhurst & Mark J. Bostock & Andras Solt & Andrew J. Y. Jones & Florian Gabriel & Aditi Tandale & Binesh Shrestha & Daniel Nietlispach, 2020. "Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14526-3
    DOI: 10.1038/s41467-020-14526-3
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    Cited by:

    1. Joanna Toporowska & Parth Kapoor & Maria Musgaard & Karolina Gherbi & Kathy Sengmany & Feng Qu & Mark Soave & Hsin-Yung Yen & Kjetil Hansen & Ali Jazayeri & Jonathan T. S. Hopper & Argyris Politis, 2024. "Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry," Nature Communications, Nature, vol. 15(1), pages 1-14, 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. Sathvik Anantakrishnan & Athi N. Naganathan, 2023. "Thermodynamic architecture and conformational plasticity of GPCRs," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. 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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