7yg0
Cryo-EM structure of human sodium-chloride cotransporter
Structural highlights
DiseaseS12A3_HUMAN Gitelman syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionS12A3_HUMAN Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the pro-inflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (By similarity).[UniProtKB:P59158][1] [2] Publication Abstract from PubMedThe sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 A for the transmembrane domain and 3.8 A for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC. Cryo-EM structure of the human sodium-chloride cotransporter NCC.,Nan J, Yuan Y, Yang X, Shan Z, Liu H, Wei F, Zhang W, Zhang Y Sci Adv. 2022 Nov 11;8(45):eadd7176. doi: 10.1126/sciadv.add7176. Epub 2022 Nov , 9. PMID:36351028[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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