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

Zoe Köck, Kilian Schnelle, Margherita Persechino, Simon Umbach, Hannes Schihada, Dovile Januliene, Kristian Parey, Steffen Pockes, Peter Kolb, Volker Dötsch, Arne Möller (), Daniel Hilger () and Frank Bernhard ()
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Zoe Köck: Goethe-University of Frankfurt/Main
Kilian Schnelle: Structural Biology section, 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
Kristian Parey: Structural Biology section, 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
Daniel Hilger: University of Marburg
Frank Bernhard: Goethe-University of Frankfurt/Main

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46096-z

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