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

Yongxiang Zhao, Kasturi Roy, Pietro Vidossich, Laura Cancedda, Marco De Vivo, Biff Forbush () and Erhu Cao ()
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Yongxiang Zhao: University of Utah School of Medicine
Kasturi Roy: Yale University School of Medicine
Pietro Vidossich: Istituto Italiano di Tecnologia
Laura Cancedda: Istituto Italiano di Tecnologia
Marco De Vivo: Istituto Italiano di Tecnologia
Biff Forbush: Yale University School of Medicine
Erhu Cao: University of Utah School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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 pathway and the conformational changes necessary for ion translocation. We also identify an NKCC1 dimer with separated transmembrane domains and extensive transmembrane and C-terminal domain interactions. We further define an N-terminal phosphoregulatory domain that interacts with the C-terminal domain, suggesting a mechanism whereby (de)phosphorylation regulates NKCC1 by tuning the strength of this domain association.

Date: 2022
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DOI: 10.1038/s41467-022-30407-3

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