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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>\n                    The human serotonin (5-HT\n                    <jats:sup>+<\/jats:sup>\n                    ) transporter SERT facilitates 5-HT\n                    <jats:sup>+<\/jats:sup>\n                    transport into cells by coupling it to Na\n                    <jats:sup>+<\/jats:sup>\n                    symport and K\n                    <jats:sup>+<\/jats:sup>\n                    antiport. Although extracellular Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    is also essential for transport, Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    cotransport has been disputed, raising questions about the role of Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    ions and why they are required. We show that Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    gradients do not impact 5-HT\n                    <jats:sup>+<\/jats:sup>\n                    accumulation, indicating that Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    does not provide a driving force for uptake and arguing against stoichiometric Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    symport. The presence of Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    had only a small effect on Na\n                    <jats:sup>+<\/jats:sup>\n                    -mediated cytoplasmic pathway closure but markedly reduced the accessibility of residues in the extracellular pathway, consistent with modulation of the outward-facing states. Simulations illustrate that Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    interacts strongly with a bound Na\n                    <jats:sup>+<\/jats:sup>\n                    ion and stabilizes helix packing on the extracellular side. We propose that Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    acts as an essential architectural cofactor by enhancing Na\n                    <jats:sup>+<\/jats:sup>\n                    affinity and interactions between helices, thereby facilitating transport-related conformational transitions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2605760123","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T19:02:04Z","timestamp":1787598124000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["The role of chloride ions in serotonin transport"],"prefix":"10.1073","volume":"123","author":[{"given":"Jiahui","family":"Huang","sequence":"first","affiliation":[{"name":"Computational Structural Biology Section, National Institutes of Neurological Disorders and Stroke, National Institutes of 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