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Structure paper

TitleStructural bases for Na-Cl cotransporter inhibition by thiazide diuretic drugs and activation by kinases.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 7006, Year 2024
Publish dateAug 14, 2024
AuthorsYongxiang Zhao / Heidi Schubert / Alan Blakely / Biff Forbush / Micholas Dean Smith / Jesse Rinehart / Erhu Cao /
PubMed AbstractThe Na-Cl cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated ...The Na-Cl cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.
External linksNat Commun / PubMed:39143061 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 2.9 Å
Structure data

43411

8vpn

EMDB-43411, PDB-8vpn:
Phosphorylated human NCC in complex with indapamide
Method: EM (single particle) / Resolution: 2.7 Å

43412

8vpp

EMDB-43412, PDB-8vpp:
Phosphorylated human NCC in complex with chlorthalidone
Method: EM (single particle) / Resolution: 2.9 Å

44979

9bwt

EMDB-44979, PDB-9bwt:
human sodium chloride cotransporter NCC S344E in the phosphorylation state and in complex with hydrochlorothiazide
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

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

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

ChemComp-HOH:
WATER

ChemComp-KLT:
2-chloro-5-[(1S)-1-hydroxy-3-oxo-2H-isoindol-1-yl]benzenesulfonamide

ChemComp-HCZ:
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Phosphorylation / a thiazide-like drug / Indapamide / Outward-open / Sodium chloride cotransporter / thiazide-like diuretics / chlorthalidone / thiazide diuretics

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