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- PDB-8qko: Connexin-43 gap junction channel in complex with mefloquine -

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Basic information

Entry
Database: PDB / ID: 8qko
TitleConnexin-43 gap junction channel in complex with mefloquine
ComponentsGap junction alpha-1 protein
KeywordsMEMBRANE PROTEIN / connexin / gap junction channel / complex / mefloquine
Function / homology
Function and homology information


gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / cell communication by electrical coupling / negative regulation of trophoblast cell migration / microtubule-based transport / gap junction hemi-channel activity / SARS-CoV-2 targets PDZ proteins in cell-cell junction / gap junction channel activity involved in cell communication by electrical coupling ...gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / cell communication by electrical coupling / negative regulation of trophoblast cell migration / microtubule-based transport / gap junction hemi-channel activity / SARS-CoV-2 targets PDZ proteins in cell-cell junction / gap junction channel activity involved in cell communication by electrical coupling / monoatomic ion transmembrane transporter activity / 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 / cardiac conduction system development / connexin complex / gap junction / Formation of annular gap junctions / cell-cell contact zone / Golgi-associated vesicle membrane / cell communication by electrical coupling involved in cardiac conduction / Gap junction degradation / bone remodeling / Gap junction assembly / gap junction channel activity / export across plasma membrane / glutamate secretion / tight junction / xenobiotic transport / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / maintenance of blood-brain barrier / positive regulation of stem cell proliferation / RHOJ GTPase cycle / RHOQ GTPase cycle / establishment of mitotic spindle orientation / efflux transmembrane transporter activity / intercalated disc / alpha-tubulin binding / positive regulation of vascular associated smooth muscle cell proliferation / tubulin binding / negative regulation of cell growth / bone development / beta-catenin binding / cellular response to amyloid-beta / cell junction / intracellular protein localization / cell-cell signaling / positive regulation of cold-induced thermogenesis / heart development / monoatomic ion transmembrane transport / spermatogenesis / positive regulation of canonical NF-kappaB signal transduction / apical plasma membrane / membrane raft / Golgi membrane / focal adhesion / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / positive regulation of gene expression / Golgi apparatus / signal transduction / mitochondrion / nucleoplasm / nucleus / plasma membrane / cytoplasm
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.73 Å
AuthorsLavriha, P. / Korkhov, V.M. / Han, Y.
Funding support Switzerland, 1items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Jan 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gap junction alpha-1 protein
B: Gap junction alpha-1 protein
C: Gap junction alpha-1 protein
D: Gap junction alpha-1 protein
E: Gap junction alpha-1 protein
F: Gap junction alpha-1 protein
G: Gap junction alpha-1 protein
H: Gap junction alpha-1 protein
I: Gap junction alpha-1 protein
J: Gap junction alpha-1 protein
K: Gap junction alpha-1 protein
L: Gap junction alpha-1 protein


Theoretical massNumber of molelcules
Total (without water)516,73612
Polymers516,73612
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Gap junction alpha-1 protein / Connexin-43 / Cx43 / Gap junction 43 kDa heart protein


Mass: 43061.336 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GJA1, GJAL / Production host: Homo sapiens (human) / References: UniProt: P17302
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: Connexin-32 gap junction channel in complex with 2-aminoethoxydipheniyl borate
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 mMTris-HCl1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
10RELION4initial Euler assignment
11RELION4final Euler assignment
12RELION4classification
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.73 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 28940 / Symmetry type: POINT

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