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Significance Cation–chloride cotransporters (CCCs) shuttle Na+, K+, and Cl− across membranes. However, it remains unclear how CCCs alternate between transport states so they can load ions from one side of… Click to show full abstract
Significance Cation–chloride cotransporters (CCCs) shuttle Na+, K+, and Cl− across membranes. However, it remains unclear how CCCs alternate between transport states so they can load ions from one side of a membrane for release into the other side. Moreover, CCCs are targeted by compounds that are used as clinical medicines for treating hypertension/edema or as pharmacological tools for dissecting CCC functions. How these pharmacological agents interact with CCCs is yet to be elucidated. Our structure of K+–Cl− cotransporter (KCC) 1 bound with the VU0463271 inhibitor highlights the extracellular ion translocation pathway as a promising site for developing CCC modulators and defines conformational changes critical for ion transport in KCC1, which are distinct from those observed in related transporter cousins.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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