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Title: Crystal Structures of Human GlyRα3 Bound to Ivermectin

Abstract

Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABA ARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive. Here we present the crystal structures of human GlyRα3 in complex with ivermectin at 2.85 and 3.08 Å resolution. Our structures allow us to explore in detail the molecular recognition of ivermectin by GlyRs, GABA ARs, and α7 nAChRs. Comparisons with previous structures reveal how the ivermectin binding expands the ion channel pore. Our results hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

Authors:
; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1373780
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 25; Journal Issue: 6
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Huang, Xin, Chen, Hao, and Shaffer, Paul L. Crystal Structures of Human GlyRα3 Bound to Ivermectin. United States: N. p., 2017. Web. doi:10.1016/j.str.2017.04.007.
Huang, Xin, Chen, Hao, & Shaffer, Paul L. Crystal Structures of Human GlyRα3 Bound to Ivermectin. United States. doi:10.1016/j.str.2017.04.007.
Huang, Xin, Chen, Hao, and Shaffer, Paul L. Thu . "Crystal Structures of Human GlyRα3 Bound to Ivermectin". United States. doi:10.1016/j.str.2017.04.007.
@article{osti_1373780,
title = {Crystal Structures of Human GlyRα3 Bound to Ivermectin},
author = {Huang, Xin and Chen, Hao and Shaffer, Paul L.},
abstractNote = {Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive. Here we present the crystal structures of human GlyRα3 in complex with ivermectin at 2.85 and 3.08 Å resolution. Our structures allow us to explore in detail the molecular recognition of ivermectin by GlyRs, GABAARs, and α7 nAChRs. Comparisons with previous structures reveal how the ivermectin binding expands the ion channel pore. Our results hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.},
doi = {10.1016/j.str.2017.04.007},
journal = {Structure},
number = 6,
volume = 25,
place = {United States},
year = {Thu Jun 01 00:00:00 EDT 2017},
month = {Thu Jun 01 00:00:00 EDT 2017}
}