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- PDB-7tti: Human KCC1 bound with VU0463271 In an outward-open state -

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Basic information

Entry
Database: PDB / ID: 7tti
TitleHuman KCC1 bound with VU0463271 In an outward-open state
ComponentsSolute carrier family 12 member 4
KeywordsTRANSPORT PROTEIN/INHIBITOR / SLC12A4 / VU0463271 / Outward-open state / TRANSPORT PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


ammonium import across plasma membrane / potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / chloride ion homeostasis / ammonium channel activity / potassium ion homeostasis / cell volume homeostasis / potassium ion import across plasma membrane / monoatomic ion transport / potassium ion transmembrane transport ...ammonium import across plasma membrane / potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / chloride ion homeostasis / ammonium channel activity / potassium ion homeostasis / cell volume homeostasis / potassium ion import across plasma membrane / monoatomic ion transport / potassium ion transmembrane transport / chloride transmembrane transport / chemical synaptic transmission / lysosomal membrane / synapse / protein kinase binding / ATP binding / membrane / plasma membrane
Similarity search - Function
K/Cl co-transporter 1 / K/Cl co-transporter / SLC12A transporter family / SLC12A transporter, C-terminal / Solute carrier family 12 / Amino acid permease/ SLC12A domain / Amino acid permease
Similarity search - Domain/homology
Chem-JUX / Solute carrier family 12 member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 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 1.1Jul 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)244,0048
Polymers241,5412
Non-polymers2,4636
Water0
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-JUX / N-cyclopropyl-N-(4-methyl-1,3-thiazol-2-yl)-2-[(6-phenylpyridazin-3-yl)sulfanyl]acetamide


Mass: 382.502 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N4OS2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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 bound with VU0463271
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: DIFFRACTION / Nominal defocus max: 3500 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.5 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 81855 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027852
ELECTRON MICROSCOPYf_angle_d1.34610804
ELECTRON MICROSCOPYf_dihedral_angle_d8.3541228
ELECTRON MICROSCOPYf_chiral_restr0.0371376
ELECTRON MICROSCOPYf_plane_restr0.0031326

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