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Elife 2020 Oct 16;9. doi: 10.7554/eLife.57870.
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High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition.

Basak S , Kumar A , Ramsey S , Gibbs E , Kapoor A , Filizola M , Chakrapani S .

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.

PubMed ID: 33063666
Article link: Elife
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aopep
GO keywords: serotonin binding [+]

Disease Ontology terms: cancer

Article Images: [+] show captions
References [+] :
Adams, PHENIX: building new software for automated crystallographic structure determination. 2002, Pubmed