2024
Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
Zhao Y, Schubert H, Blakely A, Forbush B, Smith M, Rinehart J, Cao E. Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases. Nature Communications 2024, 15: 7006. PMID: 39143061, PMCID: PMC11324901, DOI: 10.1038/s41467-024-51381-y.Peer-Reviewed Original ResearchConceptsNa+-Cl- cotransporterFamilial hyperkalemic hypertensionRenal salt retentionThiazide diuretic drugsNa+-Cl-Cotransporter inhibitionNCC activitySalt reabsorptionDiuretic drugsBlood pressureBalanced electrolyteTreat hypertensionIon translocation pathwayIon translocationThiazideHypertensionSalt retentionOrthosteric siteCo-structureCarboxyl-terminal domainKinase cascadeEdemaChlorthalidoneCotransporterTranslocation
2022
Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Zhao Y, Roy K, Vidossich P, Cancedda L, De Vivo M, Forbush B, Cao E. Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide. Nature Communications 2022, 13: 2747. PMID: 35585053, PMCID: PMC9117670, DOI: 10.1038/s41467-022-30407-3.Peer-Reviewed Original ResearchConceptsTranslocation pathwayElectron cryo-microscopy structureC-terminal domainIon translocation pathwayCation-chloride cotransporters NKCC1Transmembrane domainCotransporter NKCC1C-terminal domain interactionsStructural basisDomain interactionsRenal salt reabsorptionDomain associationConformational changesFunctional studiesIon translocationElectroneutral symportCell membraneNKCC1PathwayNKCC2DomainSalt reabsorptionTransmembraneTranslocationTransporters
2012
Loop Diuretic and Ion-binding Residues Revealed by Scanning Mutagenesis of Transmembrane Helix 3 (TM3) of Na-K-Cl Cotransporter (NKCC1)*
Somasekharan S, Tanis J, Forbush B. Loop Diuretic and Ion-binding Residues Revealed by Scanning Mutagenesis of Transmembrane Helix 3 (TM3) of Na-K-Cl Cotransporter (NKCC1)*. Journal Of Biological Chemistry 2012, 287: 17308-17317. PMID: 22437837, PMCID: PMC3366785, DOI: 10.1074/jbc.m112.356014.Peer-Reviewed Original ResearchConceptsTransmembrane helix 3Na-K-Cl cotransporterTranslocation pathwayHelix 3Homology modelTryptophan-scanning mutagenesisMutation of residuesStructural homology modelEpithelial salt transportExtracellular gateCellular chloride homeostasisScanning mutagenesisOpen conformationIntracellular endPore residuesFunctional roleIon translocationTranslocation rateResiduesMutagenesisCentral roleChloride homeostasisMutationsPathwayLarge effect