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- PDB-8ut1: Alpha7-nicotinic acetylcholine receptor bound to epibatidine -

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Basic information

Entry
Database: PDB / ID: 8ut1
TitleAlpha7-nicotinic acetylcholine receptor bound to epibatidine
ComponentsNeuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
KeywordsMEMBRANE PROTEIN / Ion channel
Function / homology
Function and homology information


sensory processing / dendrite arborization / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / response to acetylcholine / acetylcholine-gated channel complex / acetylcholine-gated monoatomic cation-selective channel activity / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity ...sensory processing / dendrite arborization / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / response to acetylcholine / acetylcholine-gated channel complex / acetylcholine-gated monoatomic cation-selective channel activity / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / dendritic spine organization / acetylcholine binding / chloride channel regulator activity / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / positive regulation of amyloid-beta formation / negative regulation of amyloid-beta formation / plasma membrane raft / modulation of excitatory postsynaptic potential / response to amyloid-beta / monoatomic ion channel activity / negative regulation of tumor necrosis factor production / positive regulation of excitatory postsynaptic potential / toxic substance binding / monoatomic ion transport / positive regulation of protein metabolic process / positive regulation of long-term synaptic potentiation / response to nicotine / electron transport chain / synapse organization / calcium channel activity / memory / cognition / intracellular calcium ion homeostasis / positive regulation of angiogenesis / calcium ion transport / amyloid-beta binding / monoatomic ion transmembrane transport / postsynaptic membrane / postsynapse / positive regulation of MAPK cascade / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / learning or memory / response to hypoxia / neuron projection / iron ion binding / positive regulation of protein phosphorylation / heme binding / positive regulation of cell population proliferation / synapse / signal transduction / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor ...Nicotinic acetylcholine receptor / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / 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
EPIBATIDINE / Chem-POV / Soluble cytochrome b562 / Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.3 Å
AuthorsBurke, S.M. / Hibbs, R.E. / Noviello, C.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS120496 United States
CitationJournal: Cell / Year: 2024
Title: Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation.
Authors: Sean M Burke / Mariia Avstrikova / Colleen M Noviello / Nuriya Mukhtasimova / Jean-Pierre Changeux / Ganesh A Thakur / Steven M Sine / Marco Cecchini / Ryan E Hibbs /
Abstract: The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological ...The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.
History
DepositionOct 30, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Mar 13, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
B: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
C: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
D: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
E: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)357,63450
Polymers336,1045
Non-polymers21,53045
Water81145
1


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

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Components

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Protein , 1 types, 5 molecules ABCDE

#1: Protein
Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion / Cytochrome b-562


Mass: 67220.797 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: CHRNA7, NACHRA7, cybC, CHRNA7 / Production host: Homo sapiens (human) / References: UniProt: P36544, UniProt: P0ABE7

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Sugars , 3 types, 15 molecules

#2: 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.: 5
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
#3: 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.: 5
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
#5: 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
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 , 5 types, 75 molecules

#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca
#6: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#7: Chemical
ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C34H56O5 / Comment: detergent*YM
#8: Chemical
ChemComp-EPJ / EPIBATIDINE / (2R)-2-(6-CHLOROPYRIDIN-3-YL)-7-AZABICYCLO[2.2.1]HEPTANE


Mass: 208.687 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C11H13ClN2 / Feature type: SUBJECT OF INVESTIGATION / Comment: alkaloid*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: Alpha7-nicotinic acetylcholine receptor bound to epibatidine
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 44 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C5 (5 fold cyclic)
3D reconstructionResolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133947 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00516875
ELECTRON MICROSCOPYf_angle_d0.67122995
ELECTRON MICROSCOPYf_dihedral_angle_d5.2282410
ELECTRON MICROSCOPYf_chiral_restr0.0432670
ELECTRON MICROSCOPYf_plane_restr0.0042845

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