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- PDB-6qvd: CryoEM structure of the human ClC-1 chloride channel, CBS state 2 -

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Basic information

Entry
Database: PDB / ID: 6qvd
TitleCryoEM structure of the human ClC-1 chloride channel, CBS state 2
ComponentsChloride channel protein 1
KeywordsMEMBRANE PROTEIN / chloride channel / CLC1 / CLCN1
Function / homology
Function and homology information


voltage-gated chloride channel activity / neuronal action potential propagation / chloride transport / chloride channel complex / chloride transmembrane transport / muscle contraction / sarcolemma / Stimuli-sensing channels / protein homodimerization activity / plasma membrane
Similarity search - Function
Chloride channel ClC-1 / Chloride channel, voltage gated / Chloride channel, core / Voltage gated chloride channel / CBS domain superfamily / CBS domain profile.
Similarity search - Domain/homology
Chloride channel protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.34 Å
AuthorsWang, K.T. / Gourdon, P.E. / Zhou, Z.H.
Funding support Denmark, 1items
OrganizationGrant numberCountry
Danish Council for Independent Research4092-00228 Denmark
CitationJournal: PLoS Biol / Year: 2019
Title: Structure of the human ClC-1 chloride channel.
Authors: Kaituo Wang / Sarah Spruce Preisler / Liying Zhang / Yanxiang Cui / Julie Winkel Missel / Christina Grønberg / Kamil Gotfryd / Erik Lindahl / Magnus Andersson / Kirstine Calloe / Pascal F ...Authors: Kaituo Wang / Sarah Spruce Preisler / Liying Zhang / Yanxiang Cui / Julie Winkel Missel / Christina Grønberg / Kamil Gotfryd / Erik Lindahl / Magnus Andersson / Kirstine Calloe / Pascal F Egea / Dan Arne Klaerke / Michael Pusch / Per Amstrup Pedersen / Z Hong Zhou / Pontus Gourdon /
Abstract: ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia ...ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue ("fast gate") known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-β-synthase (CBS) domains and the intracellular vestibule ("slow gating"). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.
History
DepositionMar 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 8, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB

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Structure visualization

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Assembly

Deposited unit
B: Chloride channel protein 1
A: Chloride channel protein 1


Theoretical massNumber of molelcules
Total (without water)217,4662
Polymers217,4662
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4990 Å2
ΔGint-54 kcal/mol
Surface area60040 Å2
MethodPISA

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Components

#1: Protein Chloride channel protein 1 / / ClC-1 / Chloride channel protein / skeletal muscle


Mass: 108733.172 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLCN1, CLC1 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P35523

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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: human Chloride Channel protein 1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.109 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 7.5 / Details: 20mM Tris ph7.5 100mM NaCl 0.2mM TCEP
Buffer componentConc.: 20 mM / Name: Tris
SpecimenConc.: 0.6 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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 9 sec. / Electron dose: 45 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter slit width: 20 eV
Image scansMovie frames/image: 60

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Processing

EM software
IDNameVersionCategory
2FREALIGNimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10RELION2initial Euler assignment
11RELION2final Euler assignment
12RELION2classification
13RELION23D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 477729
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 74048 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE / Space: REAL
Atomic model buildingPDB-ID: 5TQQ

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