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- EMDB-71664: Cryo-EM structure of human NCC with chlorthalidone (C2) -

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Basic information

Entry
Database: EMDB / ID: EMD-71664
TitleCryo-EM structure of human NCC with chlorthalidone (C2)
Map data
Sample
  • Complex: NCC-chlorthalidone complex
    • Protein or peptide: Solute carrier family 12 member 3
    • Protein or peptide: Solute carrier family 12 member 2
  • Ligand: SODIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-chloro-5-[(1R)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]benzene-1-sulfonamide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water
KeywordsMembrane transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


swim bladder inflation / Cation-coupled Chloride cotransporters / Defective SLC12A3 causes Gitelman syndrome (GS) / sodium:chloride symporter activity / chloride:monoatomic cation symporter activity / sodium:potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / sodium ion homeostasis / ammonium transmembrane transport / ammonium channel activity ...swim bladder inflation / Cation-coupled Chloride cotransporters / Defective SLC12A3 causes Gitelman syndrome (GS) / sodium:chloride symporter activity / chloride:monoatomic cation symporter activity / sodium:potassium:chloride symporter activity / Cation-coupled Chloride cotransporters / sodium ion homeostasis / ammonium transmembrane transport / ammonium channel activity / chloride ion homeostasis / ear development / renal sodium ion absorption / response to salt / potassium ion homeostasis / response to aldosterone / cell volume homeostasis / inner ear morphogenesis / sodium ion transport / potassium ion import across plasma membrane / monoatomic ion transport / chloride transmembrane transport / sodium ion transmembrane transport / basolateral plasma membrane / apical plasma membrane / extracellular exosome / ATP binding / membrane / metal ion binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Thiazide-sensitive Na-K-Cl co-transporter / Solute carrier family 12 member 1/2 / Solute carrier family 12 member 2 / 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 2 / Solute carrier family 12 member 3
Similarity search - Component
Biological speciesHomo sapiens (human) / Danio rerio (zebrafish)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsZhang J / Feng L
Funding support United States, 2 items
OrganizationGrant numberCountry
The G. Harold and Leila Y. Mathers Foundation United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2025
Title: Molecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter.
Authors: Chien-Ling Lee / Jianxiu Zhang / Liang Feng /
Abstract: Thiazide-type and thiazide-like diuretics are structurally distinct first-line antihypertensive drugs that target the sodium-chloride cotransporter (NCC) in the kidney. Thiazide-like diuretics are ...Thiazide-type and thiazide-like diuretics are structurally distinct first-line antihypertensive drugs that target the sodium-chloride cotransporter (NCC) in the kidney. Thiazide-like diuretics are reported to have better cardioprotective effects than thiazide-type diuretics, but whether this is due to differences in NCC-inhibition mechanisms, if there is any, remains unclear. To understand the molecular mechanisms of NCC inhibition by thiazide-like diuretics, we determine the structures of human NCC (hNCC) bound to two of the most widely used thiazide-like diuretics, chlorthalidone and indapamide, using cryogenic electron microscopy (cryo-EM). Structural analyses reveal shared features and distinctions between NCC-inhibition by thiazide-like and thiazide-type diuretics. Furthermore, structural comparisons allow us to identify polymorphisms in hNCC that have substantial differential effects on the potencies of specific thiazide-like and thiazide-type diuretics. Our work provides important insights into the molecular pharmacology of NCC and a blueprint for developing precision medicine to manage hypertension with thiazide-like and thiazide-type diuretics.
History
DepositionJul 10, 2025-
Header (metadata) releaseJun 3, 2026-
Map releaseJun 3, 2026-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71664.png

Downloads & links

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Map

FileDownload / File: emd_71664.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

Slices (1/3)

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: 0.25
Minimum - Maximum-0.9723267 - 1.5453329
Average (Standard dev.)0.0005723982 (±0.037381563)
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_71664_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_71664_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_71664_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : NCC-chlorthalidone complex

EntireName: NCC-chlorthalidone complex
Components
  • Complex: NCC-chlorthalidone complex
    • Protein or peptide: Solute carrier family 12 member 3
    • Protein or peptide: Solute carrier family 12 member 2
  • Ligand: SODIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-chloro-5-[(1R)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]benzene-1-sulfonamide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water

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Supramolecule #1: NCC-chlorthalidone complex

SupramoleculeName: NCC-chlorthalidone complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
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: 98.893148 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EPVRFGWVKG VMIRCMLNIW GVILYLRLPW ITAQAGIVLT WIIILLSVTV TSITGLSISA ISTNGKVKSG GTYFLISRSL GPELGGSIG LIFAFANAVG VAMHTVGFAA TVRDLLQEYG APIVDPINDI RIIGVVSVTV LLAISLAGME WESKAQVLFF L VIMVSFAN ...String:
EPVRFGWVKG VMIRCMLNIW GVILYLRLPW ITAQAGIVLT WIIILLSVTV TSITGLSISA ISTNGKVKSG GTYFLISRSL GPELGGSIG LIFAFANAVG VAMHTVGFAA TVRDLLQEYG APIVDPINDI RIIGVVSVTV LLAISLAGME WESKAQVLFF L VIMVSFAN YLVGTLIPPS EDKASKGFFS YRADIFVQNL VPDWRGPDGT FFGMFSIFFP SATGILAGAN ISGDLKDPAI AI PKGTLMA IFWTTISYLA ISATIGSCVV RDASGVLNDT VTPGWGACEG LACSYGWNFT ECTQQHSCHY GLINYYQTMS MVS GFAPLI TAGIFGATLS SALACLVSAA KVFQCLCEDQ LYPLIGFFGK GYGKNKEPVR GYLLAYAIAV AFIIIAELNT IAPI ISNFF LCSYALINFS CFHASITNSP GWRPSFQYYN KWAALFGAII SVVIMFLLTW WAALIAIGVV LFLLLYVIYK KPEVN WGSS VQAGSYNLAL SYSVGLNEVE DHIKNYRPQC LVLTGPPNFR PALVDFVGTF TRNLSLMICG HVLIGPHKQR MPELQL IAN GHTKWLNKRK IKAFYSDVIA EDLRRGVQIL MQAAGLGRMK PNILVVGFKK NWQSAHPATV EDYIGILHDA FDFNYGV CV MRMREGLNVS KMMQAHINPV FDPAEDGKEA SARVDPKALV KEEQATTIFQ SEQGKKTIDI YWLFDDGGLT LLIPYLLG R KRRWSKCKIR VFVGGQINRM DQERKAIISL LSKFRLGFHE VHILPDINQN PRAEHTKRFE DMIAPFRLND GFKDEATVN EMRRDCPWKI SDEEITKNRV KSLRQVRLNE IVLDYSRDAA LIVITLPIGR KGKCPSSLYM AWLETLSQDL RPPVILIRGN QENVLTFYC Q

UniProtKB: Solute carrier family 12 member 3

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Macromolecule #2: Solute carrier family 12 member 2

MacromoleculeName: Solute carrier family 12 member 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Danio rerio (zebrafish)
Molecular weightTheoretical: 21.497146 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSASPPISAG DYLSAPEPDA LKPAGPTPSQ SRFQVDLVTE SAGDGETTVG FDSSPPEYVA EPPPDGLRDS VSGGEKAKGR FRVVNFAAS SPDAAPAETA QNGDTVMSEG SLHSSTGGQQ HHHYDTHTNT YYLRTFGHNT IDAVPKIDFY RQTAAPLGEK L IRPTLSEL ...String:
MSASPPISAG DYLSAPEPDA LKPAGPTPSQ SRFQVDLVTE SAGDGETTVG FDSSPPEYVA EPPPDGLRDS VSGGEKAKGR FRVVNFAAS SPDAAPAETA QNGDTVMSEG SLHSSTGGQQ HHHYDTHTNT YYLRTFGHNT IDAVPKIDFY RQTAAPLGEK L IRPTLSEL HDELDKEPFE DGFANGEELT PAEESAAKDV SESK

UniProtKB: Solute carrier family 12 member 2

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Macromolecule #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: 2-chloro-5-[(1R)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]ben...

MacromoleculeName: 2-chloro-5-[(1R)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]benzene-1-sulfonamide
type: ligand / ID: 5 / Number of copies: 2 / Formula: A1CIB
Molecular weightTheoretical: 338.766 Da

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Macromolecule #6: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration8.0 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS 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: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 103392
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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