Structure and thiazide inhibition mechanism of the human Na–Cl cotransporter

Minrui Fan, Jianxiu Zhang, Chien-Ling Lee, Jinru Zhang and Liang Feng ()
Additional contact information
Minrui Fan: Stanford University School of Medicine
Jianxiu Zhang: Stanford University School of Medicine
Chien-Ling Lee: Stanford University School of Medicine
Jinru Zhang: Stanford University School of Medicine
Liang Feng: Stanford University School of Medicine

Nature, 2023, vol. 614, issue 7949, 788-793

Abstract: Abstract The sodium–chloride cotransporter (NCC) is critical for kidney physiology1. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron2,3, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome4. 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 years5–7. 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-05718-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:614:y:2023:i:7949:d:10.1038_s41586-023-05718-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-05718-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().