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- EMDB-42537: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and ... -

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Basic information

Entry
Database: EMDB / ID: EMD-42537
TitleAlpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
Map data
Sample
  • Complex: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
  • Ligand: N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl]urea
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: EPIBATIDINE
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: water
KeywordsIon Channel / modulator / PAM / MEMBRANE PROTEIN
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 / positive regulation of excitatory postsynaptic potential / negative regulation of tumor necrosis factor production / monoatomic ion channel activity / 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 / positive regulation of ERK1 and ERK2 cascade / electron transfer activity / learning or memory / response to hypoxia / neuron projection / iron ion binding / positive regulation of protein phosphorylation / positive regulation of cell population proliferation / heme binding / 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
Soluble cytochrome b562 / Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.3 Å
AuthorsBurke SM / Noviello CM / Hibbs RE
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42537.png

Downloads & links

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Map

FileDownload / File: emd_42537.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 276.224 Å		1.08 Å/pix.
x 256 pix.
= 276.224 Å		1.08 Å/pix.
x 256 pix.
= 276.224 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.079 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.38347816 - 0.6547779
Average (Standard dev.)-0.000006630554 (±0.012128151)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.224 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_42537_additional_1.map
Projections & Slices
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Half map: #2

Fileemd_42537_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_42537_half_map_2.map
Projections & Slices
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Sample components

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Entire : Alpha7-nicotinic acetylcholine receptor bound to epibatidine and ...

EntireName: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
Components
  • Complex: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
  • Ligand: N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl]urea
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: EPIBATIDINE
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: water

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Supramolecule #1: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and ...

SupramoleculeName: Alpha7-nicotinic acetylcholine receptor bound to epibatidine and NS-1738
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrom...

MacromoleculeName: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 fusion
type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.220797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI ...String:
EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI PNGEWDLVGI PGKRSERFYE CCKEPYPDVT FTVTMRRRTL YYGLNLLIPC VLISALALLV FLLPADSGEK IS LGITVLL SLTVFMLLVA EIMPATSDSV PLIAQYFAST MIIVGLSVVV TVIVLQYHHH DPDGGKMPKW TRVILLNWCA WFL RMKRPG EDKVRPACQH KQRRCSLACG RMACAGAMAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPP KLEDK SPDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLSPTHD EHLLHGGQPP EGDPD LAKI LEEVRYIANR FRCQDESEAV CSEWKFAACV VDRLCLMAFS VFTIICTIGI LMSAPNFVEA VSKDFAWSHP QFEKGG GSG GGSGGSSAWS HPQFEKGSGE GRGSLLTCGD VEENPG

UniProtKB: Neuronal acetylcholine receptor subunit alpha-7, Soluble cytochrome b562

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Macromolecule #4: N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phen...

MacromoleculeName: N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl]urea
type: ligand / ID: 4 / Number of copies: 5 / Formula: XG3
Molecular weightTheoretical: 365.135 Da

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / 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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Macromolecule #6: EPIBATIDINE

MacromoleculeName: EPIBATIDINE / type: ligand / ID: 6 / Number of copies: 5 / Formula: EPJ
Molecular weightTheoretical: 208.687 Da
Chemical component information

ChemComp-EPJ:
EPIBATIDINE / alkaloid*YM

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Macromolecule #7: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...

MacromoleculeName: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
type: ligand / ID: 7 / Number of copies: 5 / Formula: 9Z9
Molecular weightTheoretical: 544.805 Da
Chemical component information

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

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Macromolecule #8: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 8 / Number of copies: 5 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #9: water

MacromoleculeName: water / type: ligand / ID: 9 / Number of copies: 60 / 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

Concentration9.0 mg/mL
BufferpH: 7.4
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: 44.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 224633
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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