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- PDB-8zrp: Structure of nico -

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Basic information

Entry
Database: PDB / ID: 8zrp
TitleStructure of nico
Components
  • Neuronal acetylcholine receptor subunit alpha-6
  • Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / nico-bound
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
(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / Soluble cytochrome b562 / Neuronal acetylcholine receptor subunit beta-4 / Neuronal acetylcholine receptor subunit alpha-6
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsSu, J. / Yu, Z. / Zhao, Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Neuronal acetylcholine receptor subunit alpha-6
B: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
C: Neuronal acetylcholine receptor subunit alpha-6
D: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
E: Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)331,20415
Polymers326,1875
Non-polymers5,01710
Water905
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 Neuronal acetylcholine receptor subunit alpha-6


Mass: 56995.445 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNA6 / Production host: Homo sapiens (human) / References: UniProt: Q15825
#2: Protein Neuronal acetylcholine receptor subunit beta-4,Soluble cytochrome b562 / Cytochrome b-562


Mass: 70732.094 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: CHRNB4, cybC / Production host: Homo sapiens (human) / References: UniProt: P30926, UniProt: P0ABE7
#3: 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.: 8
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
#4: Chemical ChemComp-NCT / (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / (S)-(-)-NICOTINE / 3-[(2S)-1-METHYL-2-PYRROLIDINYL] PYRIDINE


Mass: 162.232 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14N2 / Feature type: SUBJECT OF INVESTIGATION / Comment: alkaloid*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
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: a6b4 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 40331 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316446
ELECTRON MICROSCOPYf_angle_d0.51122440
ELECTRON MICROSCOPYf_dihedral_angle_d10.8952251
ELECTRON MICROSCOPYf_chiral_restr0.0432696
ELECTRON MICROSCOPYf_plane_restr0.0042712

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