Jie Yu / Hongtao Zhu / Remigijus Lape / Timo Greiner / Juan Du / Wei Lü / Lucia Sivilotti / Eric Gouaux /
PubMed 要旨
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters ...Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
EMDB-20371, PDB-6plp: CryoEM structure of zebra fish alpha-1 glycine receptor YGF mutant bound with GABA in SMA, desensitized state 手法: EM (単粒子) / 解像度: 3.3 Å
EMDB-20372, PDB-6plq: CryoEM structure of zebra fish alpha-1 glycine receptor YGF mutant bound with GABA in SMA, super-open state 手法: EM (単粒子) / 解像度: 3.4 Å
EMDB-20373, PDB-6plr: CryoEM structure of zebra fish alpha-1 glycine receptor bound with glycine in nanodisc, desensitized state 手法: EM (単粒子) / 解像度: 3.2 Å
EMDB-20374, PDB-6pls: CryoEM structure of zebra fish alpha-1 glycine receptor bound with taurine in nanodisc, desensitized state 手法: EM (単粒子) / 解像度: 3.0 Å
EMDB-20376, PDB-6plu: CryoEM structure of zebra fish alpha-1 glycine receptor bound with GABA in nanodisc, desensitized state 手法: EM (単粒子) / 解像度: 3.3 Å