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bioRxiv · 10.1101/2020.03.30.016154

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.
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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. Each structure reveals a distinct interaction fingerprint between the setron and binding-pocket residues that may underlie their diverse affinities. In addition, setrons elicit varying degrees of conformational change throughout the channel that, quite surprisingly, lie along the channel activation pathway, suggesting a novel mechanism of competitive inhibition. Molecular dynamic simulations were used to assess binding-poses and the drug-target interaction dynamics. Together, this study provides a molecular basis for setron binding affinities and their inhibitory effects.

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Basak, S., Kumar, A., Ramsey, S., Gibbs, E., Kapoor, A., Filizola, M., Chakrapani, S.. 2020-04-01. High-resolution Structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition. https://doi.org/10.1101/2020.03.30.016154

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