Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide.

ABSTRACT: Cation-chloride cotransporters (CCCs) NKCC1 and NKCC2 catalyze electroneutral symport of 1 Na⁺, 1 K⁺, and 2 Cl^- across cell membranes. NKCC1 mediates trans-epithelial Cl^- secretion and regulates excitability of some neurons and NKCC2 is critical to renal salt reabsorption. Both transporters are inhibited by the so-called loop diuretics including bumetanide, and these drugs are a mainstay for treating edema and hypertension. Here, our single-particle electron cryo-microscopy structures supported by functional studies reveal an outward-facing conformation of NKCC1, showing bumetanide wedged into a pocket in the extracellular ion translocation pathway. Based on these and the previously published inward-facing structures, we define the translocation

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC9117670 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature