{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:25:30Z","timestamp":1790771130079,"version":"4.1.0"},"reference-count":61,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003194","name":"New York Stem Cell Foundation","doi-asserted-by":"publisher","award":["NYSCF-R-N145"],"award-info":[{"award-number":["NYSCF-R-N145"]}],"id":[{"id":"10.13039\/100003194","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["DP2GM123496"],"award-info":[{"award-number":["DP2GM123496"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000872","name":"McKnight Endowment Fund for Neuroscience","doi-asserted-by":"publisher","award":["043108"],"award-info":[{"award-number":["043108"]}],"id":[{"id":"10.13039\/100000872","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006211","name":"Klingenstein Third Generation Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006211","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["F32GM128263"],"award-info":[{"award-number":["F32GM128263"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006978","name":"University of California, Berkeley","doi-asserted-by":"publisher","award":["Chancellor\u2019s Fellowship"],"award-info":[{"award-number":["Chancellor\u2019s Fellowship"]}],"id":[{"id":"10.13039\/100006978","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Cation-chloride-cotransporters (CCCs) catalyze transport of Cl- with K+ and\/or Na+across 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 Mus musculus 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.<\/jats:p>","DOI":"10.7554\/elife.52505","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T08:00:22Z","timestamp":1586851222000},"source":"Crossref","is-referenced-by-count":50,"title":["Cryo-EM structure of the potassium-chloride cotransporter KCC4 in lipid nanodiscs"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6947-6053","authenticated-orcid":true,"given":"Michelle S","family":"Reid","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, United States"},{"name":"Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-9045","authenticated-orcid":true,"given":"David M","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, United States"},{"name":"Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-3406","authenticated-orcid":true,"given":"Stephen Graf","family":"Brohawn","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, United States"},{"name":"Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,4,14]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallographica Section D Biological Crystallography"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15739-1","article-title":"Molecular architecture of potassium chloride co-transporter KCC2","volume":"7","author":"Agez","year":"2017","journal-title":"Scientific Reports"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.mam.2012.05.002","article-title":"The SLC12 family of electroneutral cation-coupled chloride cotransporters","volume":"34","author":"Arroyo","year":"2013","journal-title":"Molecular Aspects of Medicine"},{"key":"bib4","article-title":"UCSF Pyem","volume-title":"GitHub","author":"Asarnow","year":"2016","unstructured":"Asarnow D. 2016. 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