8VPN

Phosphorylated human NCC in complex with indapamide

Summary for 8VPN

• Entry DOI: 10.2210/pdb8vpn/pdb
• EMDB information: 43411
• Descriptor: Solute carrier family 12 member 3, 4-chloro-N-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-3-sulfamoylbenzamide, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: phosphorylation, a thiazide-like drug, indapamide, outward-open, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 227869.56

Authors

Zhao, Y.X.,Cao, E.H. (deposition date: 2024-01-16, release date: 2024-09-04, Last modification date: 2025-05-21)

Primary citation

Zhao, Y.,Schubert, H.,Blakely, A.,Forbush, B.,Smith, M.D.,Rinehart, J.,Cao, E.
Structural bases for Na + -Cl - cotransporter inhibition by thiazide diuretic drugs and activation by kinases.
Nat Commun, 15:7006-7006, 2024

PubMed 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.

PubMed: 39143061
DOI: 10.1038/s41467-024-51381-y

Experimental method

ELECTRON MICROSCOPY (2.7 Å)