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- EMDB-33803: Cryo-EM structure of human sodium-chloride cotransporter -

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Basic information

Entry
Database: EMDB / ID: EMD-33803
TitleCryo-EM structure of human sodium-chloride cotransporter
Map dataOverall map
Sample
  • Complex: Sodium-chloride cotransporter
    • Protein or peptide: Solute carrier family 12 member 3
Keywordstransporter / cation-chloride cotransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


Defective SLC12A3 causes Gitelman syndrome (GS) / sodium:chloride symporter activity / sodium:potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / renal sodium ion absorption / sodium ion homeostasis / chloride ion homeostasis / potassium ion homeostasis / cell volume homeostasis / sodium ion transport ...Defective SLC12A3 causes Gitelman syndrome (GS) / sodium:chloride symporter activity / sodium:potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / renal sodium ion absorption / sodium ion homeostasis / chloride ion homeostasis / potassium ion homeostasis / cell volume homeostasis / sodium ion transport / response to aldosterone / potassium ion import across plasma membrane / response to dietary excess / monoatomic ion transport / sodium ion transmembrane transport / chloride transmembrane transport / apical plasma membrane / signal transduction / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol
Similarity search - Function
Thiazide-sensitive Na-K-Cl co-transporter / Amino acid permease, N-terminal / Amino acid permease N-terminal / SLC12A transporter, C-terminal / Solute carrier family 12 / Amino acid permease/ SLC12A domain / SLC12A transporter family / Amino acid permease
Similarity search - Domain/homology
Solute carrier family 12 member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsNan J / Yang XM / Shan ZY / Yuan YF / Zhang YQ
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Sci Adv / Year: 2022
Title: Cryo-EM structure of the human sodium-chloride cotransporter NCC.
Authors: Jing Nan / Yafei Yuan / Xuemei Yang / Ziyang Shan / Huihui Liu / Feiwen Wei / Wei Zhang / Yanqing Zhang /
Abstract: The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure ...The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 Å for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC.
History
DepositionJul 9, 2022-
Header (metadata) releaseNov 23, 2022-
Map releaseNov 23, 2022-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33803.png

Downloads & links

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Map

FileDownload / File: emd_33803.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationOverall map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 256 pix.
= 267.776 Å		1.05 Å/pix.
x 256 pix.
= 267.776 Å		1.05 Å/pix.
x 256 pix.
= 267.776 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.046 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.20731047 - 0.44166034
Average (Standard dev.)0.000326316 (±0.020631954)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.776 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half 1 map

Fileemd_33803_half_map_1.map
Annotationhalf 1 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half 2 map

Fileemd_33803_half_map_2.map
Annotationhalf 2 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Sodium-chloride cotransporter

EntireName: Sodium-chloride cotransporter
Components
  • Complex: Sodium-chloride cotransporter
    • Protein or peptide: Solute carrier family 12 member 3

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Supramolecule #1: Sodium-chloride cotransporter

SupramoleculeName: Sodium-chloride cotransporter / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier family 12 member 3

MacromoleculeName: Solute carrier family 12 member 3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 116.921461 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT IDVVPTYEHY ANSTQPGEPR KVRPTLADL HSFLKEGRHL HALAFDSRPS HEMTDGLVEG EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP W ITAQAGIV ...String:
MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT IDVVPTYEHY ANSTQPGEPR KVRPTLADL HSFLKEGRHL HALAFDSRPS HEMTDGLVEG EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP W ITAQAGIV LTWIIILLSV TVTSITGLSI SAISTNGKVK SGGTYFLISR SLGPELGGSI GLIFAFANAV GVAMHTVGFA ET VRDLLQE YGAPIVDPIN DIRIIGVVSV TVLLAISLAG MEWESKAQVL FFLVIMVSFA NYLVGTLIPP SEDKASKGFF SYR ADIFVQ NLVPDWRGPD GTFFGMFSIF FPSATGILAG ANISGDLKDP AIAIPKGTLM AIFWTTISYL AISATIGSCV VRDA SGVLN DTVTPGWGAC EGLACSYGWN FTECTQQHSC HYGLINYYQT MSMVSGFAPL ITAGIFGATL SSALACLVSA AKVFQ CLCE DQLYPLIGFF GKGYGKNKEP VRGYLLAYAI AVAFIIIAEL NTIAPIISNF FLCSYALINF SCFHASITNS PGWRPS FQY YNKWAALFGA IISVVIMFLL TWWAALIAIG VVLFLLLYVI YKKPEVNWGS SVQAGSYNLA LSYSVGLNEV EDHIKNY RP QCLVLTGPPN FRPALVDFVG TFTRNLSLMI CGHVLIGPHK QRMPELQLIA NGHTKWLNKR KIKAFYSDVI AEDLRRGV Q ILMQAAGLGR MKPNILVVGF KKNWQSAHPA TVEDYIGILH DAFDFNYGVC VMRMREGLNV SKMMQAHINP VFDPAEDGK EASARVDPKA LVKEEQATTI FQSEQGKKTI DIYWLFDDGG LTLLIPYLLG RKRRWSKCKI RVFVGGQINR MDQERKAIIS LLSKFRLGF HEVHILPDIN QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR VKSLRQVRLN E IVLDYSRD AALIVITLPI GRKGKCPSSL YMAWLETLSQ DLRPPVILIR GNQENVLTFY CQLEGSDEVD AGSHHHHHHH HH HGSVEDY KDDDDK

UniProtKB: Solute carrier family 12 member 3

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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

Concentration9 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum ER / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 52.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 79225
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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