8FHP

Cryo-EM structure of human NCC (class 3-1)

Summary for 8FHP

• Entry DOI: 10.2210/pdb8fhp/pdb
• EMDB information: 29098
• Descriptor: Solute carrier family 12 member 2,Solute carrier family 12 member 3 chimera, Polythiazide, SODIUM ION (3 entities in total)
• Functional Keywords: membrane transporter, membrane protein
• Biological source: Danio rerio (Zebrafish, Brachydanio rerio); More
• Total number of polymer chains: 2
• Total formula weight: 241670.07

Authors

Zhang, J.,Fan, M.,Feng, L. (deposition date: 2022-12-14, release date: 2023-02-15, Last modification date: 2024-10-16)

Primary citation

Fan, M.,Zhang, J.,Lee, C.L.,Zhang, J.,Feng, L.
Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
Nature, 614:788-793, 2023

PubMed Abstract: The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.

PubMed: 36792826
DOI: 10.1038/s41586-023-05718-0

Experimental method

ELECTRON MICROSCOPY (3.04 Å)