Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel

Lynagh, Timothy, Webb, Timothy I., Dixon, Christine L., Cromer, Brett A. and Lynch, Joseph W. (2011) Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel. Journal of Biological Chemistry, 286 51: 43913-43924. doi:10.1074/jbc.M111.262634

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Author Lynagh, Timothy
Webb, Timothy I.
Dixon, Christine L.
Cromer, Brett A.
Lynch, Joseph W.
Title Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2011-12-23
Sub-type Article (original research)
DOI 10.1074/jbc.M111.262634
Open Access Status File (Publisher version)
Volume 286
Issue 51
Start page 43913
End page 43924
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2012
Language eng
Formatted abstract
Ivermectin is an anthelmintic drug that works by activating glutamate-gated chloride channel receptors (GluClRs) in nematode parasites. GluClRs belong to the Cys-loop receptor family that also includes glycine receptor (GlyR) chloride channels. GluClRs and A288G mutant GlyRs are both activated by low nanomolar ivermectin concentrations. The crystal structure of the Caenorhabditis elegans α GluClR complexed with ivermectin has recently been published. Here, we probed ivermectin sensitivity determinants on the α1 GlyR using site-directed mutagenesis and electrophysiology. Based on a mutagenesis screen of transmembrane residues, we identified Ala288 and Pro230 as crucial sensitivity determinants. A comparison of the actions of selamectin and ivermectin suggested the benzofuran C05-OH was required for high efficacy. When taken together with docking simulations, these results supported a GlyR ivermectin binding orientation similar to that seen in the GluClR crystal structure. However, whereas the crystal structure shows that ivermectin interacts with the α GluClR via H-bonds with Leu218, Ser260, and Thr285 (α GluClR numbering), our data indicate that H-bonds with residues homologous to Ser260 and Thr285 are not important for high ivermectin sensitivity or direct agonist efficacy in A288G α1 GlyRs or three other GluClRs. Our data also suggest that van der Waals interactions between the ivermectin disaccharide and GlyR M2–M3 loop residues are unimportant for high ivermectin sensitivity. Thus, although our results corroborate the ivermectin binding orientation as revealed by the crystal structure, they demonstrate that some of the binding interactions revealed by this structure do not pertain to other highly ivermectin-sensitive Cys-loop receptors.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 23 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 24 times in Scopus Article | Citations
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