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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Author

Listed:
  • Aslihan Shenol

    (University of Copenhagen)

  • Ricardo Tenente

    (University of Copenhagen)

  • Michael Lückmann

    (University of Copenhagen)

  • Thomas M. Frimurer

    (University of Copenhagen)

  • Thue W. Schwartz

    (University of Copenhagen)

Abstract

A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

Suggested Citation

  • Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024. "Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49536-y
    DOI: 10.1038/s41467-024-49536-y
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    1. Mahbubur Rahman & Sajjad Muhammad & Mahtab A. Khan & Hui Chen & Dirk A. Ridder & Helge Müller-Fielitz & Barbora Pokorná & Tillman Vollbrandt & Ines Stölting & Roger Nadrowitz & Jürgen G Okun & Stefan , 2014. "The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    2. 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.
    3. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Benjamin Stauch & Linda C. Johansson & John D. McCorvy & Nilkanth Patel & Gye Won Han & Xi-Ping Huang & Cornelius Gati & Alexander Batyuk & Samuel T. Slocum & Andrii Ishchenko & Wolfgang Brehm & Thoma, 2019. "Structural basis of ligand recognition at the human MT1 melatonin receptor," Nature, Nature, vol. 569(7755), pages 284-288, May.
    5. Makaía M. Papasergi-Scott & Guillermo Pérez-Hernández & Hossein Batebi & Yang Gao & Gözde Eskici & Alpay B. Seven & Ouliana Panova & Daniel Hilger & Marina Casiraghi & Feng He & Luis Maul & Peter Gmei, 2024. "Time-resolved cryo-EM of G-protein activation by a GPCR," Nature, Nature, vol. 629(8014), pages 1182-1191, May.
    6. Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Benjamin Stauch & Linda C. Johansson & John D. McCorvy & Nilkanth Patel & Gye Won Han & Xi-Ping Huang & Cornelius Gati & Alexander Batyuk & Samuel T. Slocum & Andrii Ishchenko & Wolfgang Brehm & Thoma, 2019. "Publisher Correction: Structural basis of ligand recognition at the human MT1 melatonin receptor," Nature, Nature, vol. 569(7756), pages 6-6, May.
    8. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    9. Scott A. Hollingsworth & Brendan Kelly & Celine Valant & Jordan Arthur Michaelis & Olivia Mastromihalis & Geoff Thompson & A. J. Venkatakrishnan & Samuel Hertig & Peter J. Scammells & Patrick M. Sexto, 2019. "Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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