Structure and Mechanism of Glycine Receptor Elucidated by Cryo-Electron Microscopy

Abstract

Glycine receptors (GlyRs) are pentameric ion channels that mediate fast inhibitory neurotransmission. GlyRs are found in the central nervous system including the spinal cord, brain stem, and cerebellum, as well as in the retina, sperm, macrophages, hippocampus, cochlea, and liver. Due to their crucial roles in counter-balancing excitatory signals and pain signal transmission, GlyR dysfunction can lead to severe diseases, and as a result, compounds that modify GlyR activity may have tremendous therapeutic potential. Despite this potential, the development of GlyR-specific small-molecule ligands is lacking. Over the past few years, high-resolution structures of both homomeric and heteromeric GlyRs structures in various conformations have provided unprecedented details defining the pharmacology of ligand binding, subunit composition, and mechanisms of channel gating. These high-quality structures will undoubtedly help with the development of GlyR-targeted therapies.

Keywords: agonist; antagonist; cryo-EM; gating mechanism; glycine receptor; inhibitory receptor; partial agonist; potentiator.

FIGURE 1

GlyR–ligand interactions and the ion channel permeation pathway. (A), Side view of isolated homomeric GlyR dimer in cartoon representation. The principle (+) and complementary (−) subunit are colored in pink and green, respectively. The boxed area is enlarged in (B–E). (B–E) Views of binding pockets of homomeric GlyR bound with glycine (B), GABA (C), taurine (D), and strychnine (E). The ligand molecules are shown in stick representations with oxygen in red, nitrogen in blue, and carbon in cyan. The possible hydrogen bonds are shown as dashed lines. (F,G) Views of ivermectin (F) and picrotoxin (G) binding to homomeric GlyR. (H–K) Shape and size of the homomeric GlyR ion permeation pathway for apo (H), closed (I), open (J), and desensitized (K) state. M2 helices are shown as cartoons and the side chains of pore-lining residues are in ball and stick representation. Purple, green, and red spheres define radii of >3.3 Å, 1.8–3.3 Å and <1.8 Å, respectively. (L–O) Shape and size of the heteromeric GlyR ion permeation pathway for desensitized (L), semi-open (M), strychnine-bound closed state 1 (N) and strychnine-bound closed state 1 (O). The M2 helices from the α and β subunits are colored in blue and pink, respectively. (P–S) TMD of heteromeric pentamer shown in cartoon representation corresponding to (L) to (O). The α and β subunits are colored in blue and pink, respectively. The centers of mass for TMD are shown in magenta. The neighboring distances of centers of mass are denoted in Å.