Structural bases for Na+-Cl- cotransporter inhibition by thiazide diuretic drugs and activation by kinases.
Nat Commun
; 15(1): 7006, 2024 Aug 14.
Article
em En
| MEDLINE
| ID: mdl-39143061
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Simportadores de Cloreto de Sódio
/
Membro 3 da Família 12 de Carreador de Soluto
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Hidroclorotiazida
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article