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- EMDB-60064: Caenorhabditis elegans ACR-23 in apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-60064
TitleCaenorhabditis elegans ACR-23 in apo state
Map data
Sample
  • Complex: acetylcholine receptor like-23(ACR-23)
    • Protein or peptide: Betaine receptor acr-23,Soluble cytochrome b562
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsion channel / TRANSPORT PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsChen QF / Liu FL / Li TY / Gong HH / Guo F / Liu S
Funding support China, 2 items
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, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60064.png

Downloads & links

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Map

FileDownload / File: emd_60064.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 440 pix.
= 376.64 Å		0.86 Å/pix.
x 440 pix.
= 376.64 Å		0.86 Å/pix.
x 440 pix.
= 376.64 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.325
Minimum - Maximum-2.4716089 - 4.4027214
Average (Standard dev.)0.0009592756 (±0.07413698)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 376.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60064_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60064_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : acetylcholine receptor like-23(ACR-23)

EntireName: acetylcholine receptor like-23(ACR-23)
Components
  • Complex: acetylcholine receptor like-23(ACR-23)
    • Protein or peptide: Betaine receptor acr-23,Soluble cytochrome b562
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: acetylcholine receptor like-23(ACR-23)

SupramoleculeName: acetylcholine receptor like-23(ACR-23) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Molecular weightTheoretical: 67 KDa

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Macromolecule #1: Betaine receptor acr-23,Soluble cytochrome b562

MacromoleculeName: Betaine receptor acr-23,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1
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.
Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Molecular weightTheoretical: 70.582281 KDa
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: MHRIYTFLIF ISQLALGLSN NPDIPIQYEL ANNIMENYQK GLIPKVRKGS PINVTLSLQL YQIIQVNEPQ QYLLLNAWAV ERWVDQMLG WDPSEFDNET EIMARHDDIW LPDTTLYNSL EMDDSASKKL THVKLTTLGK NQGAMVELLY PTIYKISCLL N LKYFPFDT ...String:
MHRIYTFLIF ISQLALGLSN NPDIPIQYEL ANNIMENYQK GLIPKVRKGS PINVTLSLQL YQIIQVNEPQ QYLLLNAWAV ERWVDQMLG WDPSEFDNET EIMARHDDIW LPDTTLYNSL EMDDSASKKL THVKLTTLGK NQGAMVELLY PTIYKISCLL N LKYFPFDT QTCRMTFGSW SFDNSLIDYF PRTFTNGPIG LANFLENDAW SVLGTKVNRE EKKYTCCPVN YTLLHYDVVI QR KPLYYVL NLIAPTAVIT FISIIGFFTS SSVHDLRQEK ITLGITTLLS MSIMIFMVSD KMPSTSTCVP LIALFYTLMI TII SVGTLA ASSVIFVQKL GSIGNPPASK TMKWTHRIAP FVLIQMPLVM KQAYAKRAKE EKHRKRMSRK MAEAGAMADL EDNW ETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDFR HGFDILVGQI DDALKLANEG KVKEA QAAA EQLKTTRNAY IQKYLSQTSE TFAAPMDTSF TESLHIPELN RVASSNSIQS VLKPTEIQLT PYCTRNIVEL EWDWVA AVL ERVFLIFFTI CFLFSAIGIN LYGWYIWYTE NHFLFLEGTK LVPRGSSSGW SHPQFEK

UniProtKB: Betaine receptor acr-23, Soluble cytochrome b562, Betaine receptor acr-23

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.00 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K2 BASE (4k x 4k) / #0 - Average electron dose: 50.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K2 BASE (4k x 4k) / #1 - Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing #1

Image processing ID1
Image recording ID1
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 402991
Initial angle assignmentType: OTHER
Final angle assignmentType: PROJECTION MATCHING

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Image processing #2

Image processing ID2
Image recording ID2
Startup modelType of model: NONE

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Image processing #3

Image processing ID3
Image recording ID1
Startup modelType of model: NONE
Initial angle assignmentType: OTHER
Final angle assignmentType: PROJECTION MATCHING

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