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Title | Structure of the human cation-chloride cotransport KCC1 in an outward-open state. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 119, Issue 27, Page e2109083119, Year 2022 |
Publish date | Jul 5, 2022 |
![]() | Yongxiang Zhao / Jiemin Shen / Qinzhe Wang / Manuel Jose Ruiz Munevar / Pietro Vidossich / Marco De Vivo / Ming Zhou / Erhu Cao / ![]() ![]() |
PubMed Abstract | 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, ...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. |
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Methods | EM (single particle) |
Resolution | 3.25 - 3.5 Å |
Structure data | EMDB-26115, PDB-7tth: EMDB-26116, PDB-7tti: |
Chemicals | ![]() ChemComp-K: ![]() ChemComp-JUX: |
Source |
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![]() | TRANSPORT PROTEIN / SLC12A4 / Potassium-chloride transport / Inward-open state / TRANSPORT PROTEIN/INHIBITOR / VU0463271 / Outward-open state / TRANSPORT PROTEIN-INHIBITOR complex |