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Class B1 GPCR activation by an intracellular agonist

Author

Listed:
  • Kazuhiro Kobayashi

    (The University of Tokyo)

  • Kouki Kawakami

    (Tohoku University)

  • Tsukasa Kusakizako

    (The University of Tokyo)

  • Atsuhiro Tomita

    (The University of Tokyo
    Preferred Networks)

  • Michihiro Nishimura

    (The University of Tokyo)

  • Kazuhiro Sawada

    (The University of Tokyo)

  • Hiroyuki H. Okamoto

    (The University of Tokyo)

  • Suzune Hiratsuka

    (Tohoku University)

  • Gaku Nakamura

    (Tohoku University)

  • Riku Kuwabara

    (Tohoku University)

  • Hiroshi Noda

    (Chugai Pharmaceutical)

  • Hiroyasu Muramatsu

    (Chugai Pharmaceutical)

  • Masaru Shimizu

    (Chugai Pharmaceutical)

  • Tomohiko Taguchi

    (Tohoku University)

  • Asuka Inoue

    (Tohoku University)

  • Takeshi Murata

    (Chiba University)

  • Osamu Nureki

    (The University of Tokyo)

Abstract

G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and β-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1–3. However, only antagonist-bound structures are currently available1,4–6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than β-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor–transducer interface.

Suggested Citation

  • Kazuhiro Kobayashi & Kouki Kawakami & Tsukasa Kusakizako & Atsuhiro Tomita & Michihiro Nishimura & Kazuhiro Sawada & Hiroyuki H. Okamoto & Suzune Hiratsuka & Gaku Nakamura & Riku Kuwabara & Hiroshi No, 2023. "Class B1 GPCR activation by an intracellular agonist," Nature, Nature, vol. 618(7967), pages 1085-1093, June.
  • Handle: RePEc:nat:nature:v:618:y:2023:i:7967:d:10.1038_s41586-023-06169-3
    DOI: 10.1038/s41586-023-06169-3
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    Cited by:

    1. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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