{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:55:33Z","timestamp":1790319333807,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T00:00:00Z","timestamp":1515110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:p>\n                    The acetylcholine\u2010activated inward rectifier potassium current (\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    ) is constitutively active in persistent atrial fibrillation (AF). We tested the hypothesis that the blocking of\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    with the small molecule chloroquine terminates persistent AF. We used a sheep model of tachypacing\u2010induced, persistent AF, molecular modeling, electrophysiology, and structural biology approaches. The 50% inhibition\/inhibitory concentration of\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    block with chloroquine, measured by patch clamp, was 1 \u00b5M. In optical mapping of sheep hearts with persistent AF, 1 \u00b5M chloroquine restored sinus rhythm. Molecular modeling suggested that chloroquine blocked the passage of a hydrated potassium ion through the intracellular domain of Kir3.1 (a molecular correlate of\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    ) by interacting with residues D260 and F255, in proximity to I228, Q227, and L299.\n                    <jats:sup>1<\/jats:sup>\n                    H\n                    <jats:sup>15<\/jats:sup>\n                    N heteronuclear single\u2010quantum correlation of purified Kir3.1 intracellular domain confirmed the modeling results. F255, I228, Q227, and L299 underwent significant chemical\u2010shift perturbations upon drug binding. We then crystallized and solved a 2.5 \u00c5 X\u2010ray structure of Kir3.1 with F255A mutation. Modeling of chloroquine binding to the mutant channel suggested that the drug's binding to the pore becomes off centered, reducing its ability to block a hydrated potassium ion. Patch clamp validated the structural and modeling data, where the F255A and D260A mutations significantly reduced\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    block by chloroquine. With the use of numerical and structural biology approaches, we elucidated the details of how a small molecule could block an ion channel and exert antiarrhythmic effects. Chloroquine binds the\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    channel at a site formed by specific amino acids in the ion\u2010permeation pathway, leading to decreased\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>KACh<\/jats:sub>\n                    and the subsequent termination of AF.\u2014 Takemoto, Y., Slough, D. P., Meinke, G., Katnik, C., Graziano, Z. A., Chidipi, B., Reiser, M., Alhadidy, M. M., Ramirez, R., Salvador\u2010Monta\u00f1\u00e9s, O., Ennis, S., Guerrero\u2010Serna, G., Haburcak, M., Diehl, C., Cuevas, J., Jalife, J., Bohm, A., Lin, Y.\u2010S., Noujaim, S. F. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    32, 1778\u20131793 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700349r","type":"journal-article","created":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T13:10:28Z","timestamp":1511269828000},"page":"1778-1793","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule"],"prefix":"10.1096","volume":"32","author":[{"given":"Yoshio","family":"Takemoto","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Research Research Institute of Environmental Medicine, Nagoya University Nagoya Japan"},{"name":"Center for Arrhythmia Research University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana P.","family":"Slough","sequence":"additional","affiliation":[{"name":"Department of Chemistry Tufts University Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Meinke","sequence":"additional","affiliation":[{"name":"Department of Developmental, Molecular and Chemical Biology Tufts University School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Katnik","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Physiology Department University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Graziano","sequence":"additional","affiliation":[{"name":"Department of Chemistry Tufts University Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojjibabu","family":"Chidipi","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Physiology Department University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Reiser","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Physiology Department University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed M.","family":"Alhadidy","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Physiology Department University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Salvador\u2010Monta\u00f1\u00e9s","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Ennis","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Guerrero\u2010Serna","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Haburcak","sequence":"additional","affiliation":[{"name":"Department of Biology Brandeis University Waltham Massachusetts 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