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- EMDB-18468: Connexin-43 gap junction channel in complex with mefloquine -

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Basic information

Entry
Database: EMDB / ID: EMD-18468
TitleConnexin-43 gap junction channel in complex with mefloquine
Map data
Sample
  • Complex: Connexin-32 gap junction channel in complex with 2-aminoethoxydipheniyl borate
    • Protein or peptide: Gap junction alpha-1 protein
Keywordsconnexin / gap junction channel / complex / mefloquine / MEMBRANE PROTEIN
Function / homology
Function and homology information


gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of striated muscle tissue development / milk ejection reflex / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / atrial ventricular junction remodeling / cell communication by chemical coupling / cell communication by electrical coupling / neuroblast migration ...gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of striated muscle tissue development / milk ejection reflex / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / atrial ventricular junction remodeling / cell communication by chemical coupling / cell communication by electrical coupling / neuroblast migration / columnar/cuboidal epithelial cell maturation / negative regulation of trophoblast cell migration / microtubule-based transport / gap junction hemi-channel activity / regulation of bone remodeling / monoatomic ion transmembrane transporter activity / SARS-CoV-2 targets PDZ proteins in cell-cell junction / gap junction channel activity involved in cell communication by electrical coupling / contractile muscle fiber / regulation of ventricular cardiac muscle cell membrane depolarization / Oligomerization of connexins into connexons / Transport of connexins along the secretory pathway / glutathione transmembrane transporter activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / gap junction assembly / atrial cardiac muscle cell action potential / Regulation of gap junction activity / cellular response to pH / cardiac conduction system development / regulation of atrial cardiac muscle cell membrane depolarization / connexin complex / fascia adherens / Golgi-associated vesicle membrane / Formation of annular gap junctions / gap junction / cell-cell contact zone / Gap junction degradation / cell communication by electrical coupling involved in cardiac conduction / skeletal muscle tissue regeneration / bone remodeling / gap junction channel activity / Gap junction assembly / regulation of bone mineralization / export across plasma membrane / adult heart development / regulation of ventricular cardiac muscle cell membrane repolarization / tight junction / glutamate secretion / blood vessel morphogenesis / lens development in camera-type eye / intermediate filament / xenobiotic transport / embryonic digit morphogenesis / maintenance of blood-brain barrier / positive regulation of stem cell proliferation / beta-tubulin binding / RHOJ GTPase cycle / heart looping / RHOQ GTPase cycle / establishment of mitotic spindle orientation / efflux transmembrane transporter activity / intercalated disc / alpha-tubulin binding / lateral plasma membrane / T cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / tubulin binding / protein tyrosine kinase binding / neuron migration / negative regulation of cell growth / bone development / beta-catenin binding / cellular response to amyloid-beta / male gonad development / osteoblast differentiation / cell junction / protein localization / cell-cell signaling / positive regulation of cold-induced thermogenesis / heart development / scaffold protein binding / monoatomic ion transmembrane transport / spermatogenesis / positive regulation of canonical NF-kappaB signal transduction / in utero embryonic development / apical plasma membrane / membrane raft / Golgi membrane / signaling receptor binding / negative regulation of gene expression / intracellular membrane-bounded organelle / focal adhesion / positive regulation of gene expression / endoplasmic reticulum membrane / Golgi apparatus / signal transduction / mitochondrion / nucleoplasm / nucleus / plasma membrane
Similarity search - Function
Gap junction alpha-1 protein (Cx43) / Gap junction alpha-1 protein (Cx43), C-terminal / Gap junction alpha-1 protein (Cx43), alpha helix domain superfamily / Gap junction alpha-1 protein (Cx43) / Connexin, C-terminal / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain / Connexin, N-terminal domain superfamily ...Gap junction alpha-1 protein (Cx43) / Gap junction alpha-1 protein (Cx43), C-terminal / Gap junction alpha-1 protein (Cx43), alpha helix domain superfamily / Gap junction alpha-1 protein (Cx43) / 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
Gap junction alpha-1 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.73 Å
AuthorsLavriha P / Korkhov VM / Han Y
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation184951 Switzerland
CitationJournal: PLoS One / Year: 2024
Title: Mechanism of connexin channel inhibition by mefloquine and 2-aminoethoxydiphenyl borate.
Authors: Pia Lavriha / Yufei Han / Xinyue Ding / Dina Schuster / Chao Qi / Anand Vaithia / Paola Picotti / Volodymyr M Korkhov /
Abstract: Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap junction channels (GJCs). Connexin GJCs have ...Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap junction channels (GJCs). Connexin GJCs have emerged as drug targets, with small molecule connexin inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms of GJC inhibition by known small molecule connexin inhibitors remain unknown, preventing the development of more potent and connexin-specific therapeutics. Here we show that two GJC inhibitors, mefloquine (MFQ) and 2-aminoethoxydiphenyl borate (2APB) bind to Cx32 and block dye permeation across Cx32 hemichannels (HCs) and GJCs. Cryo-EM analysis shows that 2APB binds to "site A", close to the N-terminal gating helix of Cx32 GJC, restricting the entrance to the channel pore. In contrast, MFQ binds to a distinct "site M", deeply buried within the pore. MFQ binding to this site modifies the electrostatic properties of Cx32 pore. Mutagenesis of V37, a key residue located in the site M, renders Cx32 HCs and GJCs insensitive to MFQ-mediated inhibition. Moreover, our cryo-EM analysis, mutagenesis and activity assays show that MFQ targets the M site in Cx43 GJC similarly to Cx32. Taken together, our results point to a conserved inhibitor binding site in connexin channels, opening a new route for development of specific drugs targeting connexins.
History
DepositionSep 16, 2023-
Header (metadata) releaseSep 25, 2024-
Map releaseSep 25, 2024-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18468.png

Downloads & links

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Map

FileDownload / File: emd_18468.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 384 pix.
= 249.911 Å		0.65 Å/pix.
x 384 pix.
= 249.911 Å		0.65 Å/pix.
x 384 pix.
= 249.911 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.65081 Å
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Contour LevelBy AUTHOR: 0.004
Minimum - Maximum-0.0037450218 - 0.014895899
Average (Standard dev.)0.00031888348 (±0.0012410264)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.91118 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18468_msk_1.map
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Half map: half1

Fileemd_18468_half_map_1.map
Annotationhalf1
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Half map: #1

Fileemd_18468_half_map_2.map
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Sample components

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Entire : Connexin-32 gap junction channel in complex with 2-aminoethoxydip...

EntireName: Connexin-32 gap junction channel in complex with 2-aminoethoxydipheniyl borate
Components
  • Complex: Connexin-32 gap junction channel in complex with 2-aminoethoxydipheniyl borate
    • Protein or peptide: Gap junction alpha-1 protein

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Supramolecule #1: Connexin-32 gap junction channel in complex with 2-aminoethoxydip...

SupramoleculeName: Connexin-32 gap junction channel in complex with 2-aminoethoxydipheniyl borate
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gap junction alpha-1 protein

MacromoleculeName: Gap junction alpha-1 protein / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.061336 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGDWSALGKL LDKVQAYSTA GGKVWLSVLF IFRILLLGTA VESAWGDEQS AFRCNTQQPG CENVCYDKSF PISHVRFWVL QIIFVSVPT LLYLAHVFYV MRKEEKLNKK EEELKVAQTD GVNVDMHLKQ IEIKKFKYGI EEHGKVKMRG GLLRTYIISI L FKSIFEVA ...String:
MGDWSALGKL LDKVQAYSTA GGKVWLSVLF IFRILLLGTA VESAWGDEQS AFRCNTQQPG CENVCYDKSF PISHVRFWVL QIIFVSVPT LLYLAHVFYV MRKEEKLNKK EEELKVAQTD GVNVDMHLKQ IEIKKFKYGI EEHGKVKMRG GLLRTYIISI L FKSIFEVA FLLIQWYIYG FSLSAVYTCK RDPCPHQVDC FLSRPTEKTI FIIFMLVVSL VSLALNIIEL FYVFFKGVKD RV KGKSDPY HATSGALSPA KDCGSQKYAY FNGCSSPTAP LSPMSPPGYK LVTGDRNNSS CRNYNKQASE QNWANYSAEQ NRM GQAGST ISNSHAQPFD FPDDNQNSKK LAAGHELQPL AIVDQRPSSR ASSRASSRPR PDDLEI

UniProtKB: Gap junction alpha-1 protein

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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

Concentration5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 mMTris-HCl
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 130000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

15010

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.73 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 28940
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final 3D classificationSoftware - Name: RELION (ver. 4.0)

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