High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition

Abstract
Data availability
Article and author information

Abstract

Serotonin receptors (5-HT_3AR) 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-HT_3AR 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-HT_3AR, 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-HT_3AR 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.

The following data sets were generated

1. Sandip Basak
2. Sudha Chakrapani
(2020) Cryo-EM structure of 5HT3A receptor in presence of Alosetron
Protein Data Bank, 6W1J.

http://www.rcsb.org/structure/6W1J
1. Sandip Basak
2. Sudha Chakrapani
(2020) Cryo-EM structure of 5HT3A receptor in presence of Ondansetron
Protein Data Bank, 6W1M.

http://www.rcsb.org/structure/6W1M
1. Sandip Basak
2. Sudha Chakrapani
(2020) Cryo-EM structure of 5HT3A receptor in presence of Palonosetron
Protein Data Bank, 6W1Y.

http://www.rcsb.org/structure/6W1Y

The following previously published data sets were used

1. Basak S
2. Chakrapani S
(2019) https://www.rcsb.org
Protein Data Bank, 6NP0.

https://www.rcsb.org/structure/6NP0
1. Zarkadas E
2. Zhang H
3. Cai W
4. Effantin G
5. Perot J
6. Neyton J
7. Chipot C
8. Schoehn G
9. Dehez F
10. Nury H
(2020) Mouse serotonin 5HT3 receptor in complex with palonosetron
Protein Data Bank, 6Y1Z.

https://www.rcsb.org/structure/6Y1Z

Article and author information

Author details

Sandip Basak

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Arvind Kumar

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8421-8669
Steven Ramsey

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Eric Gibbs

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Abhijeet Kapoor

2Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3606-3463
Marta Filizola

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Sudha Chakrapani

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

For correspondence
Sudha.chakrapani@case.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0722-2338

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

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.