Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases

Yongxiang Zhao, Heidi Schubert, Alan Blakely, Biff Forbush, Micholas Dean Smith, Jesse Rinehart and Erhu Cao ()
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Yongxiang Zhao: University of Utah School of Medicine
Heidi Schubert: University of Utah School of Medicine
Alan Blakely: University of Utah School of Medicine
Biff Forbush: Yale University School of Medicine
Micholas Dean Smith: Knoxville
Jesse Rinehart: Yale University School of Medicine
Erhu Cao: University of Utah School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51381-y

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