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Cryo-EM structures of the human cation-chloride cotransporter KCC1.

Liu S, Chang S, Han B, Xu L, Zhang M, Zhao C, Yang W, Wang F, Li J, Delpire E, Ye S, Bai XC, Guo J
Science. 2019 366 (6464): 505-508

PMID: 31649201 · DOI:10.1126/science.aay3129

Cation-chloride cotransporters (CCCs) mediate the coupled, electroneutral symport of cations with chloride across the plasma membrane and are vital for cell volume regulation, salt reabsorption in the kidney, and γ-aminobutyric acid (GABA)-mediated modulation in neurons. Here we present cryo-electron microscopy (cryo-EM) structures of human potassium-chloride cotransporter KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-angstrom resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. KCC1 adopts an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allow us to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (17)

Amino Acid Sequence Animals Binding Sites Cryoelectron Microscopy HEK293 Cells Humans Ion Transport Mice Molecular Dynamics Simulation Oocytes Protein Domains Protein Multimerization Protein Structure, Quaternary Sequence Alignment Sodium-Potassium-Chloride Symporters Symporters Xenopus laevis

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