Yingyi Zhang1,2,3, Patricia M Dijkman1,2,4,5,6, Rongfeng Zou7, Martina Zandl-Lang8, Ricardo M Sanchez1,2, Luise Eckhardt-Strelau1, Harald Köfeler9, Horst Vogel7,10, Shuguang Yuan11, Mikhail Kudryashev12,13. 1. Max Planck Institute of Biophysics, Frankfurt am Main, Germany. 2. Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt, Frankfurt am Main, Germany. 3. Biological Cryo-EM Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. 4. Max Planck Institute of Biochemistry, Martinsried, Germany. 5. Institute of Neuropathology, University Medical Center, Göttingen, Germany. 6. Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany. 7. Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. 8. Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. 9. Core Facility Mass Spectrometry, ZMF, Medical University of Graz, Graz, Austria. 10. Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. 11. Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. shuguang.yuan@siat.ac.cn. 12. Max Planck Institute of Biophysics, Frankfurt am Main, Germany. misha.kudryashev@biophys.mpg.de. 13. Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt, Frankfurt am Main, Germany. misha.kudryashev@biophys.mpg.de.
Abstract
Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.
Pentameric ligand-gated ion channels (pLGICs) of the pan class="Chemical">Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the n>n class="Chemical">lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.
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