[English] 日本語
Yorodumi
- PDB-8v8c: Alpha7-nicotinic acetylcholine receptor time resolved bound to ep... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8v8c
TitleAlpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1
ComponentsNeuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / ION CHANNEL / NICOTINIC RECEPTOR
Function / homology
Function and homology information


sensory processing / dendrite arborization / acetylcholine receptor activity / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / short-term memory / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / positive regulation of CoA-transferase activity ...sensory processing / dendrite arborization / acetylcholine receptor activity / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / short-term memory / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / positive regulation of CoA-transferase activity / dendritic spine organization / chloride channel regulator activity / acetylcholine binding / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / synaptic transmission, cholinergic / positive regulation of amyloid-beta formation / modulation of excitatory postsynaptic potential / negative regulation of amyloid-beta formation / plasma membrane raft / response to amyloid-beta / positive regulation of excitatory postsynaptic potential / negative regulation of tumor necrosis factor production / toxic substance binding / monoatomic ion transport / positive regulation of protein metabolic process / monoatomic ion transmembrane transport / electron transport chain / response to nicotine / positive regulation of long-term synaptic potentiation / synapse organization / calcium channel activity / memory / intracellular calcium ion homeostasis / cognition / positive regulation of angiogenesis / calcium ion transport / monoatomic ion channel activity / amyloid-beta binding / postsynapse / postsynaptic membrane / positive regulation of MAPK cascade / electron transfer activity / periplasmic space / learning or memory / positive regulation of ERK1 and ERK2 cascade / response to hypoxia / neuron projection / positive regulation of protein phosphorylation / iron ion binding / synapse / positive regulation of cell population proliferation / heme binding / 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-I34 / Soluble cytochrome b562 / Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsBurke, S.M. / Noviello, C.M. / Hibbs, R.E.
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
DepositionDec 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Mar 13, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)343,16033
Polymers336,1045
Non-polymers7,05628
Water0
1


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

-
Components

-
Protein , 1 types, 5 molecules ABCDE

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


Mass: 67220.797 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Details: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage) ...Details: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage)
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNA7, NACHRA7, cybC / Production host: Homo sapiens (human) / References: UniProt: P36544, UniProt: P0ABE7

-
Sugars , 2 types, 15 molecules

#2: 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
#3: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10 / 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

-
Non-polymers , 3 types, 13 molecules

#4: Chemical
ChemComp-EPJ / EPIBATIDINE / (2R)-2-(6-CHLOROPYRIDIN-3-YL)-7-AZABICYCLO[2.2.1]HEPTANE / Epibatidine


Mass: 208.687 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C11H13ClN2 / Feature type: SUBJECT OF INVESTIGATION / Comment: alkaloid*YM
#5: Chemical
ChemComp-I34 / N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea / PNU-120,596


Mass: 311.721 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C13H14ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca

-
Details

Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

-
Sample preparation

ComponentName: Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 6.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

-
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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

-
Processing

EM software
IDNameVersionCategory
10cryoSPARCv4.2initial Euler assignment
11cryoSPARCv4.2final Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30540 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00917763
ELECTRON MICROSCOPYf_angle_d1.10224176
ELECTRON MICROSCOPYf_dihedral_angle_d8.7243125
ELECTRON MICROSCOPYf_chiral_restr0.0762769
ELECTRON MICROSCOPYf_plane_restr0.0083011

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more