Structural bases for Na + -Cl - cotransporter inhibition by thiazide diuretic drugs and activation by kinases.

Autor: Zhao Y; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.; Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, P. R. China., Schubert H; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA., Blakely A; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA., Forbush B; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA., Smith MD; Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, Knoxville, TN, 37996, USA., Rinehart J; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.; Systems Biology Institute, Yale University, New Haven, CT, USA., Cao E; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA. Erhu.Cao@biochem.utah.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 14; Vol. 15 (1), pp. 7006. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1038/s41467-024-51381-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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