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

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

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC11324901 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature