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Structure paper

TitleMolecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7740, Year 2025
Publish dateAug 20, 2025
AuthorsChien-Ling Lee / Jianxiu Zhang / Liang Feng /
PubMed AbstractThiazide-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.
External linksNat Commun / PubMed:40830368 / PubMed Central
MethodsEM (single particle)
Resolution2.79 - 3.24 Å
Structure data

71664

9pie

EMDB-71664, PDB-9pie:
Cryo-EM structure of human NCC with chlorthalidone (C2)
Method: EM (single particle) / Resolution: 3.01 Å

71665

9pif

EMDB-71665, PDB-9pif:
Cryo-EM structure of human NCC with chlorthalidone
Method: EM (single particle) / Resolution: 3.24 Å

71666

9pig

EMDB-71666, PDB-9pig:
Cryo-EM structure of human NCC with indapamide
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

ChemComp-NA:
Unknown entry

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

PDB-1cib:
STRUCTURE OF ADENYLOSUCCINATE SYNTHETASE FROM E. COLI COMPLEXED WITH GDP, IMP, HADACIDIN, AND NO3

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

ChemComp-HOH:
WATER

ChemComp-BL1:
4-chloro-N-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-3-sulfamoylbenzamide

Source
  • homo sapiens (human)
  • danio rerio (zebrafish)
KeywordsMEMBRANE PROTEIN / Membrane transporter

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