Glycine receptor mechanism elucidated by electron cryo-microscopy

摘要: The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem is linked to neurological disorders, including autism hyperekplexia. Understanding of molecular mechanisms pharmacology receptors has been hindered by a lack high-resolution structures. Here we report electron cryo-microscopy structures zebrafish α1 GlyR with strychnine, glycine, or ivermectin (glycine/ivermectin). Strychnine arrests an antagonist-bound closed ion channel state, stabilizes agonist-bound open glycine/ivermectin complex adopts potentially desensitized partially state. Relative glycine-bound strychnine expands agonist-binding pocket via outward movement C loop, promotes rearrangement extracellular transmembrane domain 'wrist' interface, leads rotation towards pore axis, occluding conduction pathway. These illuminate mechanism define rubric interpret Cys-loop receptors.