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- PDB-7tth: Human potassium-chloride cotransporter 1 in inward-open state -

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Basic information

Entry
Database: PDB / ID: 7tth
TitleHuman potassium-chloride cotransporter 1 in inward-open state
ComponentsSolute carrier family 12 member 4
KeywordsTRANSPORT PROTEIN / SLC12A4 / Potassium-chloride transport / Inward-open state
Function / homology
Function and homology information


potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / chloride ion homeostasis / potassium ion homeostasis / cell volume homeostasis / potassium ion import across plasma membrane / monoatomic ion transport / potassium ion transmembrane transport / protein serine/threonine kinase binding / chloride transmembrane transport ...potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / chloride ion homeostasis / potassium ion homeostasis / cell volume homeostasis / potassium ion import across plasma membrane / monoatomic ion transport / potassium ion transmembrane transport / protein serine/threonine kinase binding / chloride transmembrane transport / chemical synaptic transmission / lysosomal membrane / synapse / ATP binding / membrane / plasma membrane
Similarity search - Function
K/Cl co-transporter 1 / K/Cl co-transporter / SLC12A transporter, C-terminal / Solute carrier family 12 / SLC12A transporter family / Amino acid permease/ SLC12A domain / Amino acid permease
Similarity search - Domain/homology
: / Solute carrier family 12 member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsZhao, Y.X. / Cao, E.H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structure of the human cation-chloride cotransport KCC1 in an outward-open state.
Authors: Yongxiang Zhao / Jiemin Shen / Qinzhe Wang / Manuel Jose Ruiz Munevar / Pietro Vidossich / Marco De Vivo / Ming Zhou / Erhu Cao /
Abstract: Cation-chloride cotransporters (CCCs) catalyze electroneutral symport of Cl with Na and/or K across membranes. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, ...Cation-chloride cotransporters (CCCs) catalyze electroneutral symport of Cl with Na and/or K across membranes. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, maintenance of intracellular Cl concentration, and neuronal excitability. Here, we present a cryoelectron microscopy structure of human K-Cl cotransporter (KCC)1 bound with the VU0463271 inhibitor in an outward-open state. In contrast to many other amino acid-polyamine-organocation transporter cousins, our first outward-open CCC structure reveals that opening the KCC1 extracellular ion permeation path does not involve hinge-bending motions of the transmembrane (TM) 1 and TM6 half-helices. Instead, rocking of TM3 and TM8, together with displacements of TM4, TM9, and a conserved intracellular loop 1 helix, underlie alternate opening and closing of extracellular and cytoplasmic vestibules. We show that KCC1 intriguingly exists in one of two distinct dimeric states via different intersubunit interfaces. Our studies provide a blueprint for understanding the mechanisms of CCCs and their inhibition by small molecule compounds.
History
DepositionFeb 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Jun 29, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Jun 29, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Additional map / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3May 28, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Solute carrier family 12 member 4
B: Solute carrier family 12 member 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)243,3178
Polymers241,5412
Non-polymers1,7766
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Solute carrier family 12 member 4 / Electroneutral potassium-chloride cotransporter 1 / Erythroid K-Cl cotransporter 1 / hKCC1


Mass: 120770.492 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC12A4, KCC1 / Production host: Homo sapiens (human) / References: UniProt: Q9UP95
#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.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Human Potassium-chloride cotransporter 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 3500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4073077
3D reconstructionResolution: 3.25 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 79153 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312996
ELECTRON MICROSCOPYf_angle_d0.63517792
ELECTRON MICROSCOPYf_dihedral_angle_d6.8251910
ELECTRON MICROSCOPYf_chiral_restr0.0452182
ELECTRON MICROSCOPYf_plane_restr0.0042194

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