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- PDB-9z81: Stable open state sheep connexin-46 in DMPC nanodiscs at neutral pH -

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Basic information

Entry
Database: PDB / ID: 9z81
TitleStable open state sheep connexin-46 in DMPC nanodiscs at neutral pH
ComponentsGap junction alpha-3 protein
KeywordsMEMBRANE PROTEIN / connexin / gap junction / cryo-EM / pH regulation / lipid gating / large-pore channel
Function / homology
Function and homology information


gap junction-mediated intercellular transport / gap junction hemi-channel activity / connexin complex / visual perception / cell-cell signaling / plasma membrane
Similarity search - Function
Gap junction alpha-3 protein (Cx46) / Connexin, C-terminal / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain / Connexin, N-terminal domain superfamily / Connexin / Connexins signature 1. / Connexins signature 2. ...Gap junction alpha-3 protein (Cx46) / Connexin, C-terminal / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain / Connexin, N-terminal domain superfamily / Connexin / Connexins signature 1. / Connexins signature 2. / Connexin homologues / Gap junction channel protein cysteine-rich domain
Similarity search - Domain/homology
1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE / Gap junction alpha-3 protein
Similarity search - Component
Biological speciesOvis aries (sheep)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2 Å
AuthorsJarodsky, J.M. / Myers, J.B. / Reichow, S.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R35GM124779 United States
CitationJournal: Nat Commun / Year: 2026
Title: Reversible lipid-mediated pH-gating of connexin-46/50 by cryo-EM.
Authors: Joshua M Jarodsky / Janette B Myers / Steve L Reichow /
Abstract: Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to ...Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to intracellular pH changes, closing under acidic conditions to limit the spread of cytotoxic signals during cellular stress, such as ischemia. Using cryo-electron microscopy (cryo-EM), we uncover insights into the structural mechanism of pH-gating in native lens connexin-46/50 (Cx46/50) gap junctions. Mild acidification drives lipid infiltration into the channel pore, displacing the N-terminal (NT) domain and stabilizing pore closure. Lipid involvement is shown to be both essential and fully reversible. Structural transitions involve an ensemble of gated states formed through non-cooperative NT domain movement as well as minor populations of a distinct destabilized open-state. These findings provide molecular insights into pH-gating dynamics, illustrating how structural changes may regulate gap junction function under cellular stress and linking Cx46/50 dysregulation to age-related cataract formation.
History
DepositionNov 18, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gap junction alpha-3 protein
B: Gap junction alpha-3 protein
C: Gap junction alpha-3 protein
D: Gap junction alpha-3 protein
E: Gap junction alpha-3 protein
F: Gap junction alpha-3 protein
G: Gap junction alpha-3 protein
H: Gap junction alpha-3 protein
I: Gap junction alpha-3 protein
J: Gap junction alpha-3 protein
K: Gap junction alpha-3 protein
L: Gap junction alpha-3 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)739,911324
Polymers528,39612
Non-polymers211,515312
Water11,025612
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
Gap junction alpha-3 protein / Connexin-44 / Cx44


Mass: 44033.027 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: Q9TU17
#2: Chemical...
ChemComp-MC3 / 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE


Mass: 677.933 Da / Num. of mol.: 312 / Source method: obtained synthetically / Formula: C36H72NO8P / Comment: phospholipid*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 612 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: Stable open dodecameric connexin-46 gap junction in DMPC nanodiscs at neutral pH
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Ovis aries (sheep)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
22 mMEDTAC10H16N2O81
32 mMEGTAC14H24N2O101
4150 mMSodium ChlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 6142

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.4.1particle selection
4cryoSPARCv4.4.1CTF correction
10cryoSPARCv4.4.1initial Euler assignment
11cryoSPARCv4.4.1final Euler assignment
12cryoSPARCclassification
13cryoSPARCv4.4.13D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 4002015
SymmetryPoint symmetry: D6 (2x6 fold dihedral)
3D reconstructionResolution: 2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 311313 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7jkc

7jkc


Accession code: 7jkc / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2 Å

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