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Mechanism of gating and partial agonist action in the glycine receptor

View ORCID ProfileJie Yu, View ORCID ProfileHongtao Zhu, View ORCID ProfileRemigijus Lape, View ORCID ProfileTimo Greiner, View ORCID ProfileRezvan Shahoei, View ORCID ProfileYuhang Wang, View ORCID ProfileJuan Du, Wei Lü, View ORCID ProfileEmad Tajkhorshid, View ORCID ProfileLucia Sivilotti, View ORCID ProfileEric Gouaux
doi: https://doi.org/10.1101/786632
Jie Yu
1Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
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Hongtao Zhu
1Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
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Remigijus Lape
3Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK
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Timo Greiner
3Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK
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Rezvan Shahoei
4Department of Biochemistry, NIH Center for Macromolecular Modeling and Bioinformatics, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL 61801, USA
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Yuhang Wang
4Department of Biochemistry, NIH Center for Macromolecular Modeling and Bioinformatics, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL 61801, USA
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Juan Du
1Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
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Wei Lü
1Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
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Emad Tajkhorshid
4Department of Biochemistry, NIH Center for Macromolecular Modeling and Bioinformatics, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL 61801, USA
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Lucia Sivilotti
3Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK
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  • For correspondence: l.sivilotti@ucl.ac.uk gouauxe@ohsu.edu
Eric Gouaux
1Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
2Howard Hughes Medical Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
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  • For correspondence: l.sivilotti@ucl.ac.uk gouauxe@ohsu.edu
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Summary

The glycine receptor is a pentameric, neurotransmitter-activated ion channel that transitions between closed/resting, open and desensitized states. Glycine, a full agonist, produces an open channel probability (Po) of ∼1.0 while partial agonists, such as taurine and γ-amino butyric acid (GABA) yield submaximal Po values. Despite extensive studies of pentameric Cys-loop receptors, there is little knowledge of the molecular mechanisms underpinning partial agonist action and how the receptor transitions from the closed to open and to desensitized conformations. Here we use electrophysiology and molecular dynamics (MD) simulations, together with a large ensemble of single particle cryo-EM reconstructions, to show how agonists populate agonist-bound yet closed channel states, thus explaining their lesser efficacy, yet also populate agonist-bound open and desensitized states. Measurements within the neurotransmitter binding pocket, as a function of bound agonist, provide a metric to correlate the extent of agonist-induced conformational changes to open channel probability across the Cys-loop receptor family.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 30, 2019.
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Mechanism of gating and partial agonist action in the glycine receptor
Jie Yu, Hongtao Zhu, Remigijus Lape, Timo Greiner, Rezvan Shahoei, Yuhang Wang, Juan Du, Wei Lü, Emad Tajkhorshid, Lucia Sivilotti, Eric Gouaux
bioRxiv 786632; doi: https://doi.org/10.1101/786632
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Mechanism of gating and partial agonist action in the glycine receptor
Jie Yu, Hongtao Zhu, Remigijus Lape, Timo Greiner, Rezvan Shahoei, Yuhang Wang, Juan Du, Wei Lü, Emad Tajkhorshid, Lucia Sivilotti, Eric Gouaux
bioRxiv 786632; doi: https://doi.org/10.1101/786632

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