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

Si Liu, Shenghai Chang, Binming Han, Lingyi Xu, Mingfeng Zhang, Cheng Zhao, Wei Yang, Feng Wang, Jingyuan Li, Eric Delpire, Sheng Ye, Xiao Chen Bai, Jiangtao Guo

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Abstract

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 g-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.

Original languageEnglish (US)
Pages (from-to)505-508
Number of pages4
JournalScience
Volume366
Issue number6464
DOIs
StatePublished - Oct 25 2019

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Liu, S., Chang, S., Han, B., Xu, L., Zhang, M., Zhao, C., Yang, W., Wang, F., Li, J., Delpire, E., Ye, S., Bai, X. C., & Guo, J. (2019). Cryo-EM structures of the human cation-chloride cotransporter KCC1. Science, 366(6464), 505-508. https://doi.org/10.1126/science.aay3129