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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Yongxiang Zhao & Kasturi Roy & Pietro Vidossich & Laura Cancedda & Marco De Vivo & Biff Forbush & Erhu Cao, 2022. "Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30407-3
    DOI: 10.1038/s41467-022-30407-3
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    References listed on IDEAS

    as
    1. Xiaoyong Yang & Qinzhe Wang & Erhu Cao, 2020. "Structure of the human cation–chloride cotransporter NKCC1 determined by single-particle electron cryo-microscopy," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Thomas A. Chew & Benjamin J. Orlando & Jinru Zhang & Naomi R. Latorraca & Amy Wang & Scott A. Hollingsworth & Dong-Hua Chen & Ron O. Dror & Maofu Liao & Liang Feng, 2019. "Structure and mechanism of the cation–chloride cotransporter NKCC1," Nature, Nature, vol. 572(7770), pages 488-492, August.
    3. Xiaoyong Yang & Qinzhe Wang & Erhu Cao, 2020. "Author Correction: Structure of the human cation-chloride cotransporter NKCC1 determined by single-particle electron cryo-microscopy," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    4. Lynn M. Boyden & Murim Choi & Keith A. Choate & Carol J. Nelson-Williams & Anita Farhi & Hakan R. Toka & Irina R. Tikhonova & Robert Bjornson & Shrikant M. Mane & Giacomo Colussi & Marcel Lebel & Rich, 2012. "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities," Nature, Nature, vol. 482(7383), pages 98-102, February.
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    Cited by:

    1. Yongxiang Zhao & Heidi Schubert & Alan Blakely & Biff Forbush & Micholas Dean Smith & Jesse Rinehart & Erhu Cao, 2024. "Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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