TY - JOUR
T1 - Cryo-EM structures of the human cation-chloride cotransporter KCC1
AU - Liu, Si
AU - Chang, Shenghai
AU - Han, Binming
AU - Xu, Lingyi
AU - Zhang, Mingfeng
AU - Zhao, Cheng
AU - Yang, Wei
AU - Wang, Feng
AU - Li, Jingyuan
AU - Delpire, Eric
AU - Ye, Sheng
AU - Bai, Xiao Chen
AU - Guo, Jiangtao
N1 - Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/10/25
Y1 - 2019/10/25
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aay3129
DO - 10.1126/science.aay3129
M3 - Article
C2 - 31649201
AN - SCOPUS:85074080562
SN - 0036-8075
VL - 366
SP - 505
EP - 508
JO - Science
JF - Science
IS - 6464
ER -