Cation–chloride cotransporters (CCCs) catalyze electroneutral symport of Cl-with Na+and/or K+across membranes. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, maintenance of intracellular Cl-concentration, and neuronal excitability. Here, we present a cryoelectron microscopy structure of human K+–Cl-cotransporter (KCC)1 bound with the VU0463271 inhibitor in an outward-open state. In contrast to many other amino acid–polyamine–organocation transporter cousins, our first outward-open CCC structure reveals that opening the KCC1 extracellular ion permeation path does not involve hinge-bending motions of the transmembrane (TM) 1 and TM6 half-helices. Instead, rocking of TM3 and TM8, together with displacements of TM4, TM9, and a conserved intracellular loop 1 helix, underlie alternate opening and closing of extracellular and cytoplasmic vestibules. We show that KCC1 intriguingly exists in one of two distinct dimeric states via different intersubunit interfaces. Our studies provide a blueprint for understanding the mechanisms of CCCs and their inhibition by small molecule compounds.
Zhao, Yongxiang, et al. "Structure of the human cation–chloride cotransport KCC1 in an outward-open state." Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 27, Jun. 2022. https://doi.org/10.1073/pnas.2109083119
Zhao, Yongxiang, Shen, Jiemin, Wang, Qinzhe, Ruiz Munevar, Manuel Jose, Vidossich, Pietro, De Vivo, Marco, Zhou, Ming, & Cao, Erhu (2022). Structure of the human cation–chloride cotransport KCC1 in an outward-open state. Proceedings of the National Academy of Sciences of the United States of America, 119(27). https://doi.org/10.1073/pnas.2109083119
Zhao, Yongxiang, Shen, Jiemin, Wang, Qinzhe, et al., "Structure of the human cation–chloride cotransport KCC1 in an outward-open state," Proceedings of the National Academy of Sciences of the United States of America 119, no. 27 (2022), https://doi.org/10.1073/pnas.2109083119
@article{osti_1982396,
author = {Zhao, Yongxiang and Shen, Jiemin and Wang, Qinzhe and Ruiz Munevar, Manuel Jose and Vidossich, Pietro and De Vivo, Marco and Zhou, Ming and Cao, Erhu},
title = {Structure of the human cation–chloride cotransport KCC1 in an outward-open state},
annote = {Cation–chloride cotransporters (CCCs) catalyze electroneutral symport of Cl-with Na+and/or K+across membranes. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, maintenance of intracellular Cl-concentration, and neuronal excitability. Here, we present a cryoelectron microscopy structure of human K+–Cl-cotransporter (KCC)1 bound with the VU0463271 inhibitor in an outward-open state. In contrast to many other amino acid–polyamine–organocation transporter cousins, our first outward-open CCC structure reveals that opening the KCC1 extracellular ion permeation path does not involve hinge-bending motions of the transmembrane (TM) 1 and TM6 half-helices. Instead, rocking of TM3 and TM8, together with displacements of TM4, TM9, and a conserved intracellular loop 1 helix, underlie alternate opening and closing of extracellular and cytoplasmic vestibules. We show that KCC1 intriguingly exists in one of two distinct dimeric states via different intersubunit interfaces. Our studies provide a blueprint for understanding the mechanisms of CCCs and their inhibition by small molecule compounds.},
doi = {10.1073/pnas.2109083119},
url = {https://www.osti.gov/biblio/1982396},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {ISSN 0027-8424},
number = {27},
volume = {119},
place = {United States},
publisher = {National Academy of Sciences},
year = {2022},
month = {06}}
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory
(EMSL); University of Utah School of Medicine, Salt Lake City, UT (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1982396
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 27 Vol. 119; ISSN 0027-8424