9PIG

Cryo-EM structure of human NCC with indapamide

Summary for 9PIG

• Entry DOI: 10.2210/pdb9pig/pdb
• EMDB information: 71666
• Descriptor: Solute carrier family 12 member 3, Solute carrier family 12 member 2, SODIUM ION, ... (7 entities in total)
• Functional Keywords: membrane transporter, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 243015.02

Authors

Zhang, J.,Feng, L. (deposition date: 2025-07-10, release date: 2026-06-03)

Primary citation

Lee, C.L.,Zhang, J.,Feng, L.
Molecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter.
Nat Commun, 16:7740-7740, 2025

PubMed Abstract: Thiazide-type and thiazide-like diuretics are structurally distinct first-line antihypertensive drugs that target the sodium-chloride cotransporter (NCC) in the kidney. Thiazide-like diuretics are reported to have better cardioprotective effects than thiazide-type diuretics, but whether this is due to differences in NCC-inhibition mechanisms, if there is any, remains unclear. To understand the molecular mechanisms of NCC inhibition by thiazide-like diuretics, we determine the structures of human NCC (hNCC) bound to two of the most widely used thiazide-like diuretics, chlorthalidone and indapamide, using cryogenic electron microscopy (cryo-EM). Structural analyses reveal shared features and distinctions between NCC-inhibition by thiazide-like and thiazide-type diuretics. Furthermore, structural comparisons allow us to identify polymorphisms in hNCC that have substantial differential effects on the potencies of specific thiazide-like and thiazide-type diuretics. Our work provides important insights into the molecular pharmacology of NCC and a blueprint for developing precision medicine to manage hypertension with thiazide-like and thiazide-type diuretics.

PubMed: 40830368
DOI: 10.1038/s41467-025-62714-w

Experimental method

ELECTRON MICROSCOPY (2.79 Å)