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Publication Abstract from PubMed

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.

Structure of the human cation-chloride cotransport KCC1 in an outward-open state.,Zhao Y, Shen J, Wang Q, Ruiz Munevar MJ, Vidossich P, De Vivo M, Zhou M, Cao E Proc Natl Acad Sci U S A. 2022 Jul 5;119(27):e2109083119. doi: , 10.1073/pnas.2109083119. Epub 2022 Jun 27. PMID:35759661^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.