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Ondansetron and Granisetron Binding Orientation in the 5‑HT_3 Receptor Determined by Unnatural Amino Acid Mutagenesis

Duffy, Noah H. and Lester, Henry A. and Dougherty, Dennis A. (2012) Ondansetron and Granisetron Binding Orientation in the 5‑HT_3 Receptor Determined by Unnatural Amino Acid Mutagenesis. ACS Chemical Biology, 7 (10). pp. 1738-1745. ISSN 1554-8929. PMCID PMC3477246. doi:10.1021/cb300246j. https://resolver.caltech.edu/CaltechAUTHORS:20121127-104931725

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Abstract

The serotonin type 3 receptor (5-HT_3R) is a ligand-gated ion channel found in the central and peripheral nervous systems. The 5-HT_3R is a therapeutic target, and the clinically available drugs ondansetron and granisetron inhibit receptor activity. Their inhibitory action is through competitive binding to the native ligand binding site, although the binding orientation of the drugs at the receptor has been a matter of debate. Here we heterologously express mouse 5-HT_3A receptors in Xenopus oocytes and use unnatural amino acid mutagenesis to establish a cation-π interaction for both ondansetron and granisetron to tryptophan 183 in the ligand binding pocket. This cation-π interaction establishes a binding orientation for both ondansetron and granisetron within the binding pocket.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/ 10.1021/cb300246jDOIArticle
http://pubs.acs.org/doi/abs/10.1021/cb300246jPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477246PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Received: May 17, 2012. Accepted: August 8, 2012. Publication Date (Web): August 8, 2012. We thank S. Lummis for helpful discussions and input. This work was supported by the National Institutes of Health (NS 34407 and DA19375). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHDA19375
Issue or Number:10
PubMed Central ID:PMC3477246
DOI:10.1021/cb300246j
Record Number:CaltechAUTHORS:20121127-104931725
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121127-104931725
Official Citation:Ondansetron and Granisetron Binding Orientation in the 5-HT3 Receptor Determined by Unnatural Amino Acid Mutagenesis Noah H. Duffy, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Biology 2012 7 (10), 1738-1745
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35672
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:27 Nov 2012 19:02
Last Modified:09 Nov 2021 23:16

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