EMD-28892

Single-particle
2.79 Å
EMD-28892 Deposition: 17/11/2022
Map released: 07/06/2023
Last modified: 13/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-28892

Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with etomidate, desensitized-like state

EMD-28892

Single-particle
2.79 Å
EMD-28892 Deposition: 17/11/2022
Map released: 07/06/2023
Last modified: 13/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Tetronarce californica
Sample: Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with etomidate, desensitized-like state
Fitted models: 8f6y (Avg. Q-score: 0.54)

Deposition Authors: Goswami U , Rahman MM, Teng J, Hibbs RE
Structural interplay of anesthetics and paralytics on muscle nicotinic receptors.
Goswami U , Rahman MM, Teng J, Hibbs RE
(2023) Nat Commun , 14 , 3169 - 3169
PUBMED: 37264005
DOI: doi:10.1038/s41467-023-38827-5
ISSN: 2041-1723
Abstract:
General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.