High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition
- Case Western Reserve University, United States
- Icahn School of Medicine at Mount Sinai, United States
Abstract
Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Cryo-EM structure of 5HT3A receptor in presence of AlosetronProtein Data Bank, 6W1J.
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Cryo-EM structure of 5HT3A receptor in presence of OndansetronProtein Data Bank, 6W1M.
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Cryo-EM structure of 5HT3A receptor in presence of PalonosetronProtein Data Bank, 6W1Y.
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Mouse serotonin 5HT3 receptor in complex with palonosetronProtein Data Bank, 6Y1Z.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM108921,R01GM131216,R35GM134896)
- Sudha Chakrapani
American Heart Association (17POST33671152)
- Sandip Basak
American Heart Association (20POST35210394)
- Arvind Kumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Basak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition
eLife 9:e57870.
https://doi.org/10.7554/eLife.57870
