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TitleAsynchronous subunit transitions prime acetylcholine receptor activation.
Journal, issue, pagesScience, Vol. 391, Issue 6780, Page eadw1264, Year 2026
Publish dateJan 1, 2026
AuthorsMackenzie J Thompson / Christian J G Tessier / Anna Ananchenko / Camille Hénault / Johnathon R Emlaw / François Dehez / Eleftherios Zarkadas / Corrie J B daCosta / Hugues Nury / John E Baenziger /
PubMed AbstractCommunication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. For ligand-gated ion channels, agonist binding triggers rapid ...Communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. For ligand-gated ion channels, agonist binding triggers rapid transitions through intermediate states leading to a transient open-pore conformation, with these transitions shaping the postsynaptic response. In this work, we determine structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. Agonist binding to a single site stabilizes a closed structure where an entire principal agonist-binding subunit transitions to an active-like conformation, whereas the other unoccupied principal subunit remains inactive, albeit poised for activation. Uniting this intermediate structure with single-channel recordings informs a sequential activation mechanism where asynchronous subunit transitions prime the receptor for activation-a finding with implications for an entire superfamily of pentameric ligand-gated ion channels.
External linksScience / PubMed:41037590
MethodsEM (single particle)
Resolution2.8 - 3.2 Å
Structure data

EMDB-47480, PDB-9e3e:
Torpedo muscle-type nicotinic acetylcholine receptor - Diliganded State
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-47481, PDB-9e3f:
Torpedo muscle-type nicotinic acetylcholine receptor - Unliganded State
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-47482, PDB-9e3g:
Torpedo muscle-type nicotinic acetylcholine receptor - Monoliganded State
Method: EM (single particle) / Resolution: 3.13 Å

Chemicals

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

Source
  • tetronarce californica (Pacific electric ray)
KeywordsMEMBRANE PROTEIN / Nicotinic acetylcholine receptor / Ion channel / Cys-loop receptor / Pentameric ligand-gated ion channel / Neurotransmitter-gated receptor / Ligand-gated ion channel / Primed state

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