IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-53161-0.html
   My bibliography  Save this article

Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry

Author

Listed:
  • Joanna Toporowska

    (King’s College London)

  • Parth Kapoor

    (OMass Therapeutics)

  • Maria Musgaard

    (OMass Therapeutics)

  • Karolina Gherbi

    (OMass Therapeutics)

  • Kathy Sengmany

    (OMass Therapeutics)

  • Feng Qu

    (OMass Therapeutics)

  • Mark Soave

    (OMass Therapeutics)

  • Hsin-Yung Yen

    (OMass Therapeutics)

  • Kjetil Hansen

    (King’s College London)

  • Ali Jazayeri

    (OMass Therapeutics)

  • Jonathan T. S. Hopper

    (OMass Therapeutics)

  • Argyris Politis

    (King’s College London
    The University of Manchester
    The University of Manchester)

Abstract

G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development. Here, we use Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) to explore the structural dynamics of the turkey β1-adrenergic receptor (tβ1AR) bound with nine different ligands, including agonists, partial agonists, and antagonists. We find that these ligands induce distinct dynamic patterns across the receptor, which can be grouped by compound modality. Notably, full agonist binding destabilises the intracellular loop 1 (ICL1), while antagonist binding stabilises it, highlighting ICL1’s role in G protein recruitment. Our findings indicate that the conserved L72 residue in ICL1 is crucial for maintaining receptor structural integrity and stabilising the GDP-bound state. Overall, our results provide a platform for determining drug modality and highlight how HDX-MS can be used to dissect receptor ligand interaction properties and GPCR mechanism.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53161-0
    DOI: 10.1038/s41467-024-53161-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-53161-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-53161-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. Tony Warne & Maria J. Serrano-Vega & Jillian G. Baker & Rouslan Moukhametzianov & Patricia C. Edwards & Richard Henderson & Andrew G. W. Leslie & Christopher G. Tate & Gebhard F. X. Schertler, 2008. "Structure of a β1-adrenergic G-protein-coupled receptor," Nature, Nature, vol. 454(7203), pages 486-491, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    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. Yun Zhu & Bo-Ji Peng & Smriti Kumar & Lauren Stover & Jing-Yuan Chang & Jixing Lyu & Tianqi Zhang & Samantha Schrecke & Djavdat Azizov & David H. Russell & Lei Fang & Arthur Laganowsky, 2023. "Polyamine detergents tailored for native mass spectrometry studies of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    4. Sathvik Anantakrishnan & Athi N. Naganathan, 2023. "Thermodynamic architecture and conformational plasticity of GPCRs," Nature Communications, Nature, vol. 14(1), pages 1-14, 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53161-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.