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Cryo-EM structure of the human sodium-chloride cotransporter NCC.
<div class='caption-title'>Cryo-EM structure of human NCC.</div>
<div class='caption-title'>Lipids and TMD dimer interface of NCC.</div>
Nan J, Yuan Y, Yang X, Shan Z, Liu H, Wei F, Zhang W, Zhang Y
OpenAccess logo Sci Adv 8 eadd7176 (2022)
Related entries: 7yg0, 7yg1

Cited: 7 times
EuropePMC logo PMID: 36351028

Abstract

The 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 Å for the transmembrane domain and 3.8 Å 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.

Reviews citing this publication (4)

  1. Structural Pharmacology of Cation-Chloride Cotransporters. Zhao Y, Cao E. Membranes (Basel) 12 1206 (2022)
  2. Structure-function relationships in the sodium chloride cotransporter. Moreno E, Pacheco-Alvarez D, Chávez-Canales M, Elizalde S, Leyva-Ríos K, Gamba G. Front Physiol 14 1118706 (2023)
  3. The role of SLC12A family of cation-chloride cotransporters and drug discovery methodologies. Zhang S, Meor Azlan NF, Josiah SS, Zhou J, Zhou X, Jie L, Zhang Y, Dai C, Liang D, Li P, Li Z, Wang Z, Wang Y, Ding K, Wang Y, Zhang J. J Pharm Anal 13 1471-1495 (2023)
  4. Thirty years of the NaCl cotransporter: from cloning to physiology and structure. Gamba G. Am J Physiol Renal Physiol 325 F479-F490 (2023)

Articles citing this publication (3)

  1. Both chloride-binding sites are required for KCC2-mediated transport. Becker L, Hausmann J, Hartmann AM. J Biol Chem 299 105190 (2023)
  2. Cryo-EM structures of human organic anion transporting polypeptide OATP1B1. Shan Z, Yang X, Liu H, Yuan Y, Xiao Y, Nan J, Zhang W, Song W, Wang J, Wei F, Zhang Y. Cell Res (2023)
  3. Editorial Editorial: 30th anniversary of the molecular cloning and identification of the Na-Cl cotransporter, NCC. de Los Heros P, Ellison DH, Gamba G. Front Physiol 14 1221806 (2023)


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