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- EMDB-29103: Cryo-EM structure of human NCC -

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Basic information

Entry
Database: EMDB / ID: EMD-29103
TitleCryo-EM structure of human NCC
Map data
Sample
  • Complex: NCC
    • Protein or peptide: Solute carrier family 12 member 3
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
KeywordsMembrane transporter / 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 / sodium ion homeostasis / chloride ion homeostasis / renal sodium ion absorption / response to salt / potassium ion homeostasis / response to aldosterone ...Defective SLC12A3 causes Gitelman syndrome (GS) / sodium:chloride symporter activity / sodium:potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / sodium ion homeostasis / chloride ion homeostasis / renal sodium ion absorption / response to salt / potassium ion homeostasis / response to aldosterone / cell volume homeostasis / sodium ion transport / potassium ion import across plasma membrane / monoatomic ion transport / sodium ion transmembrane transport / chloride transmembrane transport / apical plasma membrane / 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 / SLC12A transporter family / Amino acid permease/ SLC12A domain / 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: 3.02 Å
AuthorsZhang J / Fan M / Feng L
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2023
Title: Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
Authors: Minrui Fan / Jianxiu Zhang / Chien-Ling Lee / Jinru Zhang / Liang Feng /
Abstract: The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in the NCC cause ...The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.
History
DepositionDec 15, 2022-
Header (metadata) releaseFeb 15, 2023-
Map releaseFeb 15, 2023-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29103.png

Downloads & links

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Map

FileDownload / File: emd_29103.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å

Surface

Projections

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Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.6911169 - 2.1167274
Average (Standard dev.)-0.00094730203 (±0.045075785)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 275.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29103_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29103_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_29103_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : NCC

EntireName: NCC
Components
  • Complex: NCC
    • Protein or peptide: Solute carrier family 12 member 3
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION

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Supramolecule #1: NCC

SupramoleculeName: NCC / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 113.279719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRDFGYND IDVVPTYEHY ANDTQPGEPR KVRPTLADL HSFLKQEGRH LHALAFDSRP SHEMTDGLVE GEAGTSSEKN PEEPVRFGWV NGVMIRCMLN IWGVILYLRL P WITAQAGI ...String:
MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRDFGYND IDVVPTYEHY ANDTQPGEPR KVRPTLADL HSFLKQEGRH LHALAFDSRP SHEMTDGLVE GEAGTSSEKN PEEPVRFGWV NGVMIRCMLN IWGVILYLRL P WITAQAGI VLTWIIILLS VTVTSITGLS ISAISTNGKV KSGGTYFLIS RSLGPELGGS IGLIFAFANA VGVAMHTVGF AE TVRDLLQ EYGAPIVDPI NDIRIIGVVS VTVLLAISLA GMEWESKAQV LFFLVIMVSF ANYLVGTLIP PSEDKASKGF FSY RADIFV QNLVPDWRGP DGTFFGMFSI FFPSATGILA GANISGDLKD PAIAIPKGTL MAIFWTTISY LAISATIGSC VVRD ASGVL NDTVTPGWGA CEGLACSYGW NFTECTQQHS CHYGLINYYQ TMSMVSGFAP LITAGIFGAT LSSALACLVS AAKVF QCLC EDQLYPLIGF FGKGYGKNKE PVRGYLLAYA IAVAFIIIAE LNTIAPIISN FFLCSYALIN FSCFHASITN SPGWRP SFQ YYNKWAALFG AIISVVIMFL LTWWAALIAI GVVLFLLLYV IYKKPEVNWG SSVQAGSYNL ALSYSVGLNE VEDHIKN YR PQCLVLTGPP NFRPALVDFV GTFTRNLSLM ICGHVLIGPH KQRMPELQLI ANGHTKWLNK RKIKAFYSDV IAEDLRRG V QILMQAAGLG RMKPNILVVG FKKNWQSAHP ATVEDYIGIL HDAFDFNYGV CVMRMREGLN VSKMMQAHIN PVFDPAEDG KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG GLTLLIPYLL GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLG FHEVHILPDI NQNPRAEHTK RFEDMIAPFR LNDGFKDEAT VNEMRRDCPW KISDEEITKN RVKSLRQVRL N EIVLDYSR DAALIVITLP IGRKGKCPSS LYMAWLETLS QDLRPPVILI RGNQENVLTF YCQ

UniProtKB: Solute carrier family 12 member 3

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Macromolecule #2: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 2 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #3: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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

Concentration12 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 338556
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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