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Structure paper

TitleStructural mechanism of muscle nicotinic receptor desensitization and block by curare.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 4, Page 386-394, Year 2022
Publish dateMar 17, 2022
AuthorsMd Mahfuzur Rahman / Tamara Basta / Jinfeng Teng / Myeongseon Lee / Brady T Worrell / Michael H B Stowell / Ryan E Hibbs /
PubMed AbstractBinding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three- ...Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three-dimensional structure how agonists and antagonists alter nicotinic acetylcholine receptor conformation. We used the muscle-type receptor from the Torpedo ray to first define the structure of the receptor in a resting, activatable state. We then determined the receptor structure bound to the agonist carbachol, which stabilizes an asymmetric, closed channel desensitized state. We find conformational changes in a peripheral membrane helix are tied to recovery from desensitization. To probe mechanisms of antagonism, we obtained receptor structures with the active component of curare, a poison arrow toxin and precursor to modern muscle relaxants. d-Tubocurarine stabilizes the receptor in a desensitized-like state in the presence and absence of agonist. These findings define the transitions between resting and desensitized states and reveal divergent means by which antagonists block channel activity of the muscle-type nicotinic receptor.
External linksNat Struct Mol Biol / PubMed:35301478 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.18 Å
Structure data

EMDB-25202, PDB-7smm:
Cryo-EM structure of Torpedo acetylcholine receptor in apo form
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-25205, PDB-7smq:
Cryo-EM structure of Torpedo acetylcholine receptor in apo form with added cholesterol
Method: EM (single particle) / Resolution: 2.74 Å

EMDB-25206, PDB-7smr:
Cryo-EM structure of Torpedo acetylcholine receptor in complex with carbachol, desensitized state
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-25207, PDB-7sms:
Cryo-EM structure of Torpedo acetylcholine receptor in complex with d-tubocurarine
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-25208, PDB-7smt:
Cryo-EM structure of Torpedo acetylcholine receptor in complex with d-tubocurarine and carbachol
Method: EM (single particle) / Resolution: 2.56 Å

Chemicals

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

ChemComp-CLR:
CHOLESTEROL

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

ChemComp-DD9:
nonane

ChemComp-HOH:
WATER

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

ChemComp-TC9:
D-TUBOCURARINE / alkaloid*YM

Source
  • tetronarce californica (Pacific electric ray)
KeywordsTRANSPORT PROTEIN / acetylcholine receptor / nicotinic receptor / Torpedo / Cys-loop receptor / ion channel / muscle-type nicotinic receptor

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