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- EMDB-60401: Structure of nico -

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Basic information

Entry
Database: EMDB / ID: EMD-60401
TitleStructure of nico
Map data
Sample
  • Complex: a6b4
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-6
    • Protein or peptide: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
  • Ligand: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE
  • Ligand: water
Keywordsnico-bound / MEMBRANE PROTEIN
Function / homology
Function and homology information


synaptic transmission involved in micturition / positive regulation of transmission of nerve impulse / Highly sodium permeable postsynaptic acetylcholine nicotinic receptors / Highly calcium permeable nicotinic acetylcholine receptors / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / cholinergic synapse / acetylcholine-gated channel complex / regulation of neurotransmitter secretion / regulation of smooth muscle contraction ...synaptic transmission involved in micturition / positive regulation of transmission of nerve impulse / Highly sodium permeable postsynaptic acetylcholine nicotinic receptors / Highly calcium permeable nicotinic acetylcholine receptors / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / cholinergic synapse / acetylcholine-gated channel complex / regulation of neurotransmitter secretion / regulation of smooth muscle contraction / neuromuscular synaptic transmission / dopaminergic synapse / behavioral response to nicotine / acetylcholine-gated monoatomic cation-selective channel activity / synaptic transmission, cholinergic / acetylcholine receptor signaling pathway / postsynaptic specialization membrane / ligand-gated monoatomic ion channel activity / regulation of dopamine secretion / tertiary granule membrane / membrane depolarization / smooth muscle contraction / neuronal action potential / specific granule membrane / monoatomic ion transport / presynaptic modulation of chemical synaptic transmission / locomotory behavior / response to nicotine / electron transport chain / presynaptic membrane / monoatomic ion transmembrane transport / chemical synaptic transmission / postsynaptic membrane / periplasmic space / electron transfer activity / neuron projection / iron ion binding / synapse / heme binding / Neutrophil degranulation / signal transduction / membrane / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / 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 ...Nicotinic acetylcholine receptor / 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
Soluble cytochrome b562 / Neuronal acetylcholine receptor subunit beta-4 / Neuronal acetylcholine receptor subunit alpha-6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsSu J / Yu Z / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Commun / Year: 2025
Title: Molecular insights into the α6β4 nicotinic acetylcholine receptor function and ligand recognition.
Authors: Jiawei Su / Zhuoya Yu / Zhengji Yin / Zixuan Zhang / Jun Zhao / Yufei Meng / Renjie Li / Yiwei Gao / Hongwei Zhang / Rilei Yu / Yan Zhao /
Abstract: The α6β4 nicotinic acetylcholine receptor (nAChR) is found in the sensory neurons of dorsal root ganglia. It is a promising therapeutic target for pain. However, the difficultly of heterologous ...The α6β4 nicotinic acetylcholine receptor (nAChR) is found in the sensory neurons of dorsal root ganglia. It is a promising therapeutic target for pain. However, the difficultly of heterologous functional expression of α6β4 receptor has hindered the discovery of drugs that target it. Here, we functionally express the human α6β4 receptor and determine the cryo-EM structures of α6β4 receptor in complex with its agonists, nicotine and the preclinical drug tebanicline. These structures were captured in non-conducting desensitized states. We elucidate that the stoichiometry of α- and β- subunits in the α6β4 receptor is 2α6:3β4. Furthermore, we identify the binding pockets for nicotine and tebanicline, demonstrating the essential residues contributing to ligand affinity and providing detailed molecular insights into why these agonists have different binding affinities despite both occupying the orthosteric site of the α6β4 receptor. These structures offer significant molecular insight into the function and ligand recognition of α6β4 receptor.
History
DepositionJun 5, 2024-
Header (metadata) releaseApr 30, 2025-
Map releaseApr 30, 2025-
UpdateApr 30, 2025-
Current statusApr 30, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60401.png

Downloads & links

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Map

FileDownload / File: emd_60401.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.5578362 - 0.7943926
Average (Standard dev.)-0.00024053572 (±0.0187542)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 340.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60401_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60401_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60401_half_map_2.map
Projections & Slices
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Sample components

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Entire : a6b4

EntireName: a6b4
Components
  • Complex: a6b4
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-6
    • Protein or peptide: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
  • Ligand: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE
  • Ligand: water

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Supramolecule #1: a6b4

SupramoleculeName: a6b4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Neuronal acetylcholine receptor subunit alpha-6

MacromoleculeName: Neuronal acetylcholine receptor subunit alpha-6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.995445 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLTSKGQGFL HGGLCLWLCV FTPFFKGCVG CATEERLFHK LFSHYNQFIR PVENVSDPVT VHFEVAITQL ANVDEVNQIM ETNLWLRHI WNDYKLRWDP MEYDGIETLR VPADKIWKPD IVLYNNAVGD FQVEGKTKAL LKYNGMITWT PPAIFKSSCP M DITFFPFD ...String:
MLTSKGQGFL HGGLCLWLCV FTPFFKGCVG CATEERLFHK LFSHYNQFIR PVENVSDPVT VHFEVAITQL ANVDEVNQIM ETNLWLRHI WNDYKLRWDP MEYDGIETLR VPADKIWKPD IVLYNNAVGD FQVEGKTKAL LKYNGMITWT PPAIFKSSCP M DITFFPFD HQNCSLKFGS WTYDKAEIDL LIIGSKVDMN DFWENSEWEI IDASGYKHDI KYNCCEEIYT DITYSFYIRR LP MFYTINL IIPCLFISFL TVLVFYLPSD CGEKVTLCIS VLLSLTVFLL VITETIPSTS LVVPLVGEYL LFTMIFVTLS IVV TVFVLN IHYRTPTTHT MPRWVKTVFL KLLPQVLLMR WPLDKTRGTG SDAVPRGLGS GSLEVLFQGP GGSGSGSLEV LFQG PGGSL QWVVENSEHS PELADILNEV QYIANRFRSQ NETKEVEDDW KYVAMVVDRV FLWVFIIVCV FGTAGLFLQP LLGNT GKSS ASASASASAH HHHHHHH

UniProtKB: Neuronal acetylcholine receptor subunit alpha-6, Neuronal acetylcholine receptor subunit alpha-6

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Macromolecule #2: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562

MacromoleculeName: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.732094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRRAPSLVLF FLVALCGRGN CRVANAEEKL MDDLLNKTRY NNLIRPATSS SQLISIKLQL SLAQLISVNE REQIMTTNVW LKQEWTDYR LTWNSSRYEG VNILRIPAKR IWLPDIVLYN NADGTYEVSV YTNLIVRSNG SVLWLPPAIY KSACKIEVKY F PFDQQNCT ...String:
MRRAPSLVLF FLVALCGRGN CRVANAEEKL MDDLLNKTRY NNLIRPATSS SQLISIKLQL SLAQLISVNE REQIMTTNVW LKQEWTDYR LTWNSSRYEG VNILRIPAKR IWLPDIVLYN NADGTYEVSV YTNLIVRSNG SVLWLPPAIY KSACKIEVKY F PFDQQNCT LKFRSWTYDH TEIDMVLMTP TASMDDFTPS GEWDIVALPG RRTVNPQDPS YVDVTYDFII KRKPLFYTIN LI IPCVLTT LLAILVFYLP SDCGEKMTLC ISVLLALTFF LLLISKIVPP TSLDVPLIGK YLMFTMVLVT FSIVTSVCVL NVH HRSPST HTMAPWVKRC FLHKLPTFLF MKRPGPDSSP ARAFGSGSLE VLFQGPGGSA DLEDNWETLN DNLKVIEKAD NAAQ VKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKY LGSG SLEVLFQGPG GSPAGSTPVA IPRDFWLRSS GRFRPDLAEI LEEVSYIANR FRNQDEDQSV VEDWKYVAMV VDRLFL WVF MFVCVLGTVG LFLPPLFQTH AASEGPYAAQ RDSASASASA SAWSHPQFEK GGGSGGGSGG SAWSHPQFEK

UniProtKB: Neuronal acetylcholine receptor subunit beta-4, Soluble cytochrome b562, Neuronal acetylcholine receptor subunit beta-4

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Macromolecule #4: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE

MacromoleculeName: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / type: ligand / ID: 4 / Number of copies: 2 / Formula: NCT
Molecular weightTheoretical: 162.232 Da
Chemical component information

ChemComp-NCT:
(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / alkaloid*YM

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 5 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 40331
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: ANGULAR RECONSTITUTION

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