5VDI

Crystal Structure of Human Glycine Receptor alpha-3 Mutant N38Q Bound to AM-3607, Glycine, and Ivermectin

Summary for 5VDI

• Entry DOI: 10.2210/pdb5vdi/pdb
• Related: 5VDH
• Descriptor: Glycine receptor subunit alpha-3, (3S,3aS,9bS)-2-[(2H-1,3-benzodioxol-5-yl)sulfonyl]-3,5-dimethyl-1,2,3,3a,5,9b-hexahydro-4H-pyrrolo[3,4-c][1,6]naphthyridin-4-one, GLYCINE, ... (6 entities in total)
• Functional Keywords: ligand-gated ion channel, neurotransmitter receptor, membrane protein, cys-loop receptor, transport protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell junction, synapse, postsynaptic cell membrane ; Multi-pass membrane protein : O75311
• Total number of polymer chains: 5
• Total formula weight: 216442.15

Authors

Shaffer, P.L.,Huang, X.,Chen, H. (deposition date: 2017-04-03, release date: 2017-05-24, Last modification date: 2023-10-04)

Primary citation

Huang, X.,Chen, H.,Shaffer, P.L.
Crystal Structures of Human GlyR alpha 3 Bound to Ivermectin.
Structure, 25:945-950.e2, 2017

PubMed Abstract: Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABARs), 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, GABARs, 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.

PubMed: 28479061
DOI: 10.1016/j.str.2017.04.007

Experimental method

X-RAY DIFFRACTION (3.1 Å)