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Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody

Author

Listed:
  • Yosuke Toyoda

    (Tsinghua University
    Tsinghua University
    Kyoto University)

  • Angqi Zhu

    (Tsinghua University
    Tsinghua University)

  • Fang Kong

    (Tsinghua University
    Tsinghua University)

  • Sisi Shan

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Jiawei Zhao

    (Tsinghua University
    Tsinghua University)

  • Nan Wang

    (Tsinghua University
    Tsinghua University)

  • Xiaoou Sun

    (Tsinghua University
    Tsinghua University)

  • Linqi Zhang

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Chuangye Yan

    (Tsinghua University
    Tsinghua University)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Xiangyu Liu

    (Tsinghua University
    Tsinghua University)

Abstract

The α1A-adrenergic receptor (α1AAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. α1AAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human α1AAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 Å to 3.5 Å. Our active and inactive α1AAR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of α1AAR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.

Suggested Citation

  • Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39310-x
    DOI: 10.1038/s41467-023-39310-x
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