Crystal Structures of Human GlyRα3 Bound to Ivermectin

Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), gamma-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal alpha 7-nicotinic receptors (alpha 7 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 GlyR alpha 1 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 GlyR3 in complex with ivermectin at 2.85 and 3.08 angstrom resolution. Our structures allow us to explore in detail the molecular recognition of ivermectin by GlyRs, GABAARs, and alpha 7 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.