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TitleShape-shifting conotoxins reveal divergent pore-targeting mechanisms in nicotinic receptors.
Journal, issue, pagesStructure, Year 2025
Publish dateDec 29, 2025
AuthorsBiddut Bhattacharjee / Colleen M Noviello / Md Mahfuzur Rahman / John P Mayer / Joanna Gajewiak / J Michael McIntosh / Ryan E Hibbs / Michael H B Stowell /
PubMed AbstractThe neuronal α7 nicotinic acetylcholine receptor (α7-nAChR) and muscle-type nicotinic acetylcholine receptor (mt-nAChR) are pivotal in synaptic signaling within the brain and the neuromuscular ...The neuronal α7 nicotinic acetylcholine receptor (α7-nAChR) and muscle-type nicotinic acetylcholine receptor (mt-nAChR) are pivotal in synaptic signaling within the brain and the neuromuscular junction respectively. Additionally, they are both targets of a wide range of drugs and toxins. Here, we utilize cryo-EM to delineate structures of these nAChRs in complex with the conotoxins ImI and ImII from Conus imperialis. Despite nominal sequence differences, ImI and ImII exhibit discrete binding preferences and adopt drastically different conformational states upon binding. ImI engages the orthosteric sites of α7-nAChR, while ImII forms distinct pore-bound complexes with both α7-nAChR and mt-nAChR. Strikingly, ImII adopts a compact globular conformation that binds as a monomer to the α7-nAChR pore and as an oblate dimer to the mt-nAChR pore. These structures advance our understanding of nAChR-ligand interactions and the subtle sequence variations that result in dramatically altered functional outcomes in small peptide toxins.
External linksStructure / PubMed:41468893 / PubMed Central
MethodsEM (single particle)
Resolution2.96 - 3.1 Å
Structure data

EMDB-49897, PDB-9nx0:
Alpha7-nicotinic acetylcholine receptor bound to conotoxin ImI
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-49898, PDB-9nx1:
Alpha7-nicotinic acetylcholine receptor bound to conotoxin ImII
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-49899, PDB-9nx2:
Muscle-type nicotinic acetylcholine receptor bound to conotoxin ImII
Method: EM (single particle) / Resolution: 2.96 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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

ChemComp-EPJ:
EPIBATIDINE / alkaloid*YM

ChemComp-CCE:
2-[(AMINOCARBONYL)OXY]-N,N,N-TRIMETHYLETHANAMINIUM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • conus imperialis (invertebrata)
  • tetronarce californica (Pacific electric ray)
KeywordsMEMBRANE PROTEIN / ion channel / toxin

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