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- PDB-8zfl: Caenorhabditis elegans ACR-23 in apo state -

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Basic information

Entry
Database: PDB / ID: 8zfl
TitleCaenorhabditis elegans ACR-23 in apo state
ComponentsBetaine receptor acr-23,Soluble cytochrome b562
KeywordsTRANSPORT PROTEIN / ion channel
Function / homology
Function and homology information


Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / Neurotransmitter receptors and postsynaptic signal transmission / excitatory extracellular ligand-gated monoatomic ion channel activity / transmembrane transporter complex / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / electron transport chain / transmembrane signaling receptor activity / monoatomic ion transmembrane transport / chemical synaptic transmission ...Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / Neurotransmitter receptors and postsynaptic signal transmission / excitatory extracellular ligand-gated monoatomic ion channel activity / transmembrane transporter complex / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / electron transport chain / transmembrane signaling receptor activity / monoatomic ion transmembrane transport / chemical synaptic transmission / periplasmic space / electron transfer activity / postsynapse / neuron projection / iron ion binding / synapse / heme binding / plasma membrane
Similarity search - Function
Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel ...Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
Similarity search - Domain/homology
Betaine receptor acr-23 / Soluble cytochrome b562
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
Shimwellia blattae (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsChen, Q.F. / Liu, F.L. / Li, T.Y. / Gong, H.H. / Guo, F. / Liu, S.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071202 China
National Natural Science Foundation of China (NSFC)32100129 China
CitationJournal: EMBO J / Year: 2024
Title: Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.
Authors: Fenglian Liu / Tianyu Li / Huihui Gong / Fei Tian / Yan Bai / Haowei Wang / Chonglin Yang / Yang Li / Fei Guo / Sheng Liu / Qingfeng Chen /
Abstract: Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics ...Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.
History
DepositionMay 8, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 13, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Betaine receptor acr-23,Soluble cytochrome b562
B: Betaine receptor acr-23,Soluble cytochrome b562
C: Betaine receptor acr-23,Soluble cytochrome b562
D: Betaine receptor acr-23,Soluble cytochrome b562
E: Betaine receptor acr-23,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)358,26120
Polymers352,9115
Non-polymers5,35015
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Betaine receptor acr-23,Soluble cytochrome b562 / Acetylcholine receptor subunit alpha-type acr-23 / Cytochrome b-562


Mass: 70582.281 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Details: Residues 387-500 correspond to the bril expression tag. Residues 599-603 and 610-612 correspond to flexible linkers, residues 604-609 correspond to the thrombin cleavage site, and residues ...Details: Residues 387-500 correspond to the bril expression tag. Residues 599-603 and 610-612 correspond to flexible linkers, residues 604-609 correspond to the thrombin cleavage site, and residues 613-620 correspond to the strep ll tag.
Source: (gene. exp.) Caenorhabditis elegans (invertebrata), (gene. exp.) Shimwellia blattae (bacteria)
Gene: acr-23, 5E130, F59B1.9, cybC
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: G5EG88, UniProt: P0ABE7
#2: 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.: 10
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
#3: 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.: 5 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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
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: acetylcholine receptor like-23(ACR-23) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.067 MDa / Experimental value: NO
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Cell: sf9
Buffer solutionpH: 8
SpecimenConc.: 4 mg/ml / Embedding 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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector model
1150GATAN K2 BASE (4k x 4k)
2150GATAN K2 BASE (4k x 4k)

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Processing

Image processing
IDImage recording-ID
11
22
31
CTF correction
IDEM image processing-IDType
11PHASE FLIPPING AND AMPLITUDE CORRECTION
22PHASE FLIPPING AND AMPLITUDE CORRECTION
33PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 402991 / Symmetry type: POINT
RefinementHighest resolution: 2.61 Å

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