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Cryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment

Author

Listed:
  • Zoe Köck

    (Goethe-University of Frankfurt/Main)

  • Kilian Schnelle

    (Structural Biology section, University of Osnabrück
    University of Osnabrück)

  • Margherita Persechino

    (University of Marburg)

  • Simon Umbach

    (Goethe-University of Frankfurt/Main)

  • Hannes Schihada

    (University of Marburg)

  • Dovile Januliene

    (Structural Biology section, University of Osnabrück
    University of Osnabrück)

  • Kristian Parey

    (Structural Biology section, University of Osnabrück
    University of Osnabrück)

  • Steffen Pockes

    (University of Regensburg)

  • Peter Kolb

    (University of Marburg)

  • Volker Dötsch

    (Goethe-University of Frankfurt/Main)

  • Arne Möller

    (Structural Biology section, University of Osnabrück
    University of Osnabrück)

  • Daniel Hilger

    (University of Marburg)

  • Frank Bernhard

    (Goethe-University of Frankfurt/Main)

Abstract

Here we describe the cryo-electron microscopy structure of the human histamine 2 receptor (H2R) in an active conformation with bound histamine and in complex with Gs heterotrimeric protein at an overall resolution of 3.4 Å. The complex was generated by cotranslational insertion of the receptor into preformed nanodisc membranes using cell-free synthesis in E. coli lysates. Structural comparison with the inactive conformation of H2R and the inactive and Gq-coupled active state of H1R together with structure-guided functional experiments reveal molecular insights into the specificity of ligand binding and G protein coupling for this receptor family. We demonstrate lipid-modulated folding of cell-free synthesized H2R, its agonist-dependent internalization and its interaction with endogenously synthesized H1R and H2R in HEK293 cells by applying a recently developed nanotransfer technique.

Suggested Citation

  • Zoe Köck & Kilian Schnelle & Margherita Persechino & Simon Umbach & Hannes Schihada & Dovile Januliene & Kristian Parey & Steffen Pockes & Peter Kolb & Volker Dötsch & Arne Möller & Daniel Hilger & Fr, 2024. "Cryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46096-z
    DOI: 10.1038/s41467-024-46096-z
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    References listed on IDEAS

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    1. Jie Yin & Kuang-Yui M. Chen & Mary J. Clark & Mahdi Hijazi & Punita Kumari & Xiao-chen Bai & Roger K. Sunahara & Patrick Barth & Daniel M. Rosenbaum, 2020. "Structure of a D2 dopamine receptor–G-protein complex in a lipid membrane," Nature, Nature, vol. 584(7819), pages 125-129, August.
    2. M. J. Strohman & S. Maeda & D. Hilger & M. Masureel & Y. Du & B. K. Kobilka, 2019. "Local membrane charge regulates β2 adrenergic receptor coupling to Gi3," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Ryan G Coleman & Michael Carchia & Teague Sterling & John J Irwin & Brian K Shoichet, 2013. "Ligand Pose and Orientational Sampling in Molecular Docking," PLOS ONE, Public Library of Science, vol. 8(10), pages 1-19, October.
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