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-Structure paper
Title | Cryo-EM structure of the potassium-chloride cotransporter KCC4 in lipid nanodiscs. |
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Journal, issue, pages | Elife, Vol. 9, Year 2020 |
Publish date | Apr 14, 2020 |
Authors | Michelle S Reid / David M Kern / Stephen Graf Brohawn / |
PubMed Abstract | Cation-chloride-cotransporters (CCCs) catalyze transport of Cl with K and/or Naacross cellular membranes. CCCs play roles in cellular volume regulation, neural development and function, audition, ...Cation-chloride-cotransporters (CCCs) catalyze transport of Cl with K and/or Naacross cellular membranes. CCCs play roles in cellular volume regulation, neural development and function, audition, regulation of blood pressure, and renal function. CCCs are targets of clinically important drugs including loop diuretics and their disruption has been implicated in pathophysiology including epilepsy, hearing loss, and the genetic disorders Andermann, Gitelman, and Bartter syndromes. Here we present the structure of a CCC, the K-Cl cotransporter (KCC) KCC4, in lipid nanodiscs determined by cryo-EM. The structure, captured in an inside-open conformation, reveals the architecture of KCCs including an extracellular domain poised to regulate transport activity through an outer gate. We identify binding sites for substrate K and Cl ions, demonstrate the importance of key coordinating residues for transporter activity, and provide a structural explanation for varied substrate specificity and ion transport ratio among CCCs. These results provide mechanistic insight into the function and regulation of a physiologically important transporter family. |
External links | Elife / PubMed:32286222 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.65 Å |
Structure data | EMDB-20807, PDB-6ukn: |
Chemicals | ChemComp-K: ChemComp-CL: |
Source |
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Keywords | TRANSPORT PROTEIN / Potassium chloride cotransporter / SLC12 |