Crystal Structures of Human GlyRα3 Bound to Ivermectin.
Structure (London, England : 1993)
confidence
Key findings
Crystal structures of human GlyRα3 bound to ivermectin reveal molecular recognition and pore expansion; structural basis for GlyR modulator design.
View source on PubMed (PMID 28479061) ↗
- Population
- Human GlyRα3 (in vitro crystal structure study)
- Blinding
- not_reported
- Controls
- none
- Drug class
- antiparasitic
Full abstract
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.