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- PDB-8f6y: Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in ... -

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Basic information

Entry
Database: PDB / ID: 8f6y
TitleCryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with etomidate, desensitized-like state
Components(Acetylcholine receptor subunit ...) x 4
KeywordsTRANSPORT PROTEIN/INHIBITOR / acetylcholine receptor / nicotinic receptor / Torpedo / Cys-loop receptor / ion channel / muscle-type nicotinic receptor / TRANSPORT PROTEIN-INHIBITOR complex / General anesthetic / Inhibitor
Function / homology
Function and homology information


acetylcholine-gated monoatomic cation-selective channel activity / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / transmembrane signaling receptor activity / postsynaptic membrane
Similarity search - Function
Neurotransmitter-gated ion-channel transmembrane domain / Nicotinic acetylcholine receptor / Acetylcholine Binding Protein; Chain: A, / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor ...Neurotransmitter-gated ion-channel transmembrane domain / Nicotinic acetylcholine receptor / Acetylcholine Binding Protein; Chain: A, / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Distorted Sandwich / Up-down Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
CHOLINE ION / CHOLESTEROL / nonane / Chem-POV / Etomidate / Acetylcholine receptor subunit alpha / Acetylcholine receptor subunit beta / Acetylcholine receptor subunit gamma / Acetylcholine receptor subunit delta
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsGoswami, U. / Rahman, M.M. / Teng, J. / Hibbs, R.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural interplay of anesthetics and paralytics on muscle nicotinic receptors.
Authors: Umang Goswami / Md Mahfuzur Rahman / Jinfeng Teng / Ryan E Hibbs /
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 ...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.
History
DepositionNov 17, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
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Revision 1.1Jun 14, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acetylcholine receptor subunit alpha
B: Acetylcholine receptor subunit delta
C: Acetylcholine receptor subunit beta
D: Acetylcholine receptor subunit alpha
E: Acetylcholine receptor subunit gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)277,88726
Polymers267,1565
Non-polymers10,73121
Water905
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Acetylcholine receptor subunit ... , 4 types, 5 molecules ADBCE

#1: Protein Acetylcholine receptor subunit alpha


Mass: 49766.793 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P02710
#2: Protein Acetylcholine receptor subunit delta


Mass: 57554.633 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P02718
#3: Protein Acetylcholine receptor subunit beta


Mass: 53731.773 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P02712
#4: Protein Acetylcholine receptor subunit gamma


Mass: 56335.684 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P02714

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Sugars , 4 types, 7 molecules

#5: Polysaccharide alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c6-d1_d6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#11: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 19 molecules

#8: Chemical ChemComp-V8D / Etomidate


Mass: 244.289 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H16N2O2 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-CHT / CHOLINE ION


Mass: 104.171 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H14NO
#10: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#12: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#13: Chemical ChemComp-DD9 / nonane


Mass: 128.255 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H20
#14: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with etomidate, desensitized-like state
Type: COMPLEX / Entity ID: #1-#4 / Source: NATURAL
Source (natural)Organism: Tetronarce californica (Pacific electric ray)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 500 nm / Nominal defocus min: 2500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
4RELION3.1CTF correction
8PHENIXmodel refinement
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1413199 / Symmetry type: POINT

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