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U.S.A."],"published-print":{"date-parts":[[2024,2,27]]},"abstract":"<jats:p>The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that regulates transepithelial salt and fluid homeostasis. CFTR dysfunction leads to reduced chloride secretion into the mucosal lining of epithelial tissues, thereby causing the inherited disease cystic fibrosis. Although several structures of CFTR are available, our understanding of the ion-conduction pathway is incomplete. In particular, the route that connects the cytosolic vestibule with the extracellular space has not been clearly defined, and the structure of the open pore remains elusive. Furthermore, although many residues have been implicated in altering the selectivity of CFTR, the structure of the \u201cselectivity filter\u201d has yet to be determined. In this study, we identify a chloride-binding site at the extracellular ends of transmembrane helices 1, 6, and 8, where a dehydrated chloride is coordinated by residues G103, R334, F337, T338, and Y914. Alterations to this site, consistent with its function as a selectivity filter, affect ion selectivity, conductance, and open channel block. This selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads us to propose a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer.<\/jats:p>","DOI":"10.1073\/pnas.2316673121","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T13:41:18Z","timestamp":1708522878000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Structural identification of a selectivity filter in CFTR"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8916-4241","authenticated-orcid":false,"given":"Jesper","family":"Levring","sequence":"first","affiliation":[{"name":"Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2075-4283","authenticated-orcid":false,"given":"Jue","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065"},{"name":"HHMI, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1382316"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115450"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90446-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/352628a0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)42339-3"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911061107"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3849"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2772657"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198305193082002"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.18.6167"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1604905113"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.04.001"},{"key":"e_1_3_4_14_2","unstructured":"The Clinical and Functional TRanslation of CFTR (CFTR2). https:\/\/www.cftr2.org\/mutations_history. 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Brogioli A new open source software for the calculation of the liquid junction potential between two solutions according to the stationary Nernst-Planck equation. arXiv [Preprint] (2014). https:\/\/doi.org\/10.48550\/arXiv.1403.3640 (Accessed 27 July 2023)."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2316673121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T13:42:19Z","timestamp":1708522939000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2316673121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,21]]},"references-count":95,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,2,27]]}},"alternative-id":["10.1073\/pnas.2316673121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2316673121","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.11.561906","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,21]]},"assertion":[{"value":"2023-09-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2316673121"}}