Structural basis for human NKCC1 inhibition by loop diuretic drugs.

ABSTRACT: Na⁺-K⁺-Cl^- cotransporters functions as an anion importers, regulating trans-epithelial chloride secretion, cell volume, and renal salt reabsorption. Loop diuretics, including furosemide, bumetanide, and torsemide, antagonize both NKCC1 and NKCC2, and are first-line medicines for the treatment of edema and hypertension. NKCC1 activation by the molecular crowding sensing WNK kinases is critical if cells are to combat shrinkage during hypertonic stress; however, how phosphorylation accelerates NKCC1 ion transport remains unclear. Here, we present co-structures of phospho-activated NKCC1 bound with furosemide, bumetanide, or torsemide showing that furosemide and bumetanide utilize a carboxyl group to coordinate and co-occlude a K⁺, whereas torsemide

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC11876703 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature