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Structure paper

TitleStructural mechanisms of α7 nicotinic receptor allosteric modulation and activation.
Journal, issue, pagesCell, Vol. 187, Issue 5, Page 1160-1176.e21, Year 2024
Publish dateFeb 29, 2024
AuthorsSean M Burke / Mariia Avstrikova / Colleen M Noviello / Nuriya Mukhtasimova / Jean-Pierre Changeux / Ganesh A Thakur / Steven M Sine / Marco Cecchini / Ryan E Hibbs /
PubMed AbstractThe α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological ...The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.
External linksCell / PubMed:38382524 / PubMed Central
MethodsEM (single particle)
Resolution2.19 - 3.31 Å
Structure data

EMDB-42526, PDB-8ut1:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-42537, PDB-8utb:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-42841, PDB-8uzj:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine and ivermectin
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-43012, PDB-8v80:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine and (-)-TQS
Method: EM (single particle) / Resolution: 2.34 Å

EMDB-43015, PDB-8v82:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine and PNU-120596
Method: EM (single particle) / Resolution: 2.61 Å

EMDB-43025, PDB-8v86:
Alpha7-nicotinic acetylcholine receptor bound to GAT107
Method: EM (single particle) / Resolution: 2.47 Å

EMDB-43030, PDB-8v88:
Alpha7-nicotinic acetylcholine receptor bound to epibatidine and GAT107
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-43031, PDB-8v89:
Alpha7-nicotinic acetylcholine receptor time resolved resting state
Method: EM (single particle) / Resolution: 2.53 Å

EMDB-43032, PDB-8v8a:
Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 desensitized intermediate state
Method: EM (single particle) / Resolution: 2.19 Å

EMDB-43034, PDB-8v8c:
Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-43035, PDB-8v8d:
Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 2
Method: EM (single particle) / Resolution: 3.31 Å

Chemicals

ChemComp-CA:
Unknown entry

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-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-EPJ:
EPIBATIDINE / alkaloid*YM

ChemComp-HOH:
WATER


ChemComp, No image

ChemComp-XG3:
Unknown entry

ChemComp-IVM:
(2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17 / antiparasitic*YM


ChemComp, No image

ChemComp-YLR:
Unknown entry

ChemComp-I34:
N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea


ChemComp, No image

ChemComp-YLI:
Unknown entry

ChemComp-R16:
HEXADECANE

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Ion channel / modulator / PAM / NICOTINIC RECEPTOR

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