8vpp

Phosphorylated human NCC in complex with chlorthalidone

spinqualitylabelsall models 8vpp, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8vpp is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.9Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function J3QSS1_HUMAN Publication Abstract from PubMed 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. Structural bases for Na(+)-Cl(-) cotransporter inhibition by thiazide diuretic drugs and activation by kinases.,Zhao Y, Schubert H, Blakely A, Forbush B, Smith MD, Rinehart J, Cao E Nat Commun. 2024 Aug 14;15(1):7006. doi: 10.1038/s41467-024-51381-y. PMID:39143061 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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