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Structure paper

TitleStructural basis for human NKCC1 inhibition by loop diuretic drugs.
Journal, issue, pagesEMBO J, Vol. 44, Issue 5, Page 1540-1562, Year 2025
Publish dateJan 28, 2025
AuthorsYongxiang Zhao / Pietro Vidossich / Biff Forbush / Junfeng Ma / Jesse Rinehart / Marco De Vivo / Erhu Cao /
PubMed AbstractNa-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 ...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 encroaches and expels the K from the site. We also found that an amino-terminal segment of NKCC1, once phosphorylated, interacts with the carboxyl-terminal domain, and together, they engage with intracellular ion exit and appear to be poised to facilitate rapid ion translocation. Together, these findings enhance our understanding of NKCC-mediated epithelial ion transport and the molecular mechanisms of its inhibition by loop diuretics.
External linksEMBO J / PubMed:39875725 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 2.7 Å
Structure data

45081

9c0e

EMDB-45081, PDB-9c0e:
Phosphorylated human NKCC1_K289NA492E in complex with furosemide
Method: EM (single particle) / Resolution: 2.7 Å

45083

9c0g

EMDB-45083, PDB-9c0g:
Phosphorylated human NKCC1 in complex with torsemide
Method: EM (single particle) / Resolution: 2.6 Å

45084

9c0h

EMDB-45084, PDB-9c0h:
Phosphorylated human NKCC1 in complex with bumetanide
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-FUN:
5-(AMINOSULFONYL)-4-CHLORO-2-[(2-FURYLMETHYL)AMINO]BENZOIC ACID / medication*YM

ChemComp-K:
Unknown entry

ChemComp-CL:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-MG:
Unknown entry

PDB-1atu:
UNCLEAVED ALPHA-1-ANTITRYPSIN

ChemComp-HOH:
WATER

ChemComp-82U:
3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid / medication*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Sodium potassium chloride cotransporter / phosphorylation / outward-open state / furosemide / outward-open / torsemide / bumetanide

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