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Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
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Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
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Journal Article
Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
2024
Overview
The Na
+
-Cl
−
cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.
The Na
+
-Cl
−
cotransporter (NCC) drives salt reabsorption in the kidney. Here the authors determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they occlude the NCC ion translocation pathway.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/57
/ Animals
/ Chlorthalidone - pharmacology
/ Drugs
/ Edema
/ Humanities and Social Sciences
/ Humans
/ Hydrochlorothiazide - chemistry
/ Hydrochlorothiazide - pharmacology
/ Kidneys
/ Kinases
/ Protein Kinases - metabolism
/ Protein Serine-Threonine Kinases
/ Salts
/ Science
/ Science & Technology - Other Topics
/ Sodium Chloride Symporter Inhibitors - pharmacology
/ Solute Carrier Family 12, Member 3 - chemistry
