{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T06:34:00Z","timestamp":1789454040663,"version":"build-2803163510"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"ANID | Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1190203"],"award-info":[{"award-number":["1190203"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM150272"],"award-info":[{"award-number":["R01GM150272"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["RO1GM030376"],"award-info":[{"award-number":["RO1GM030376"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["21200592"],"award-info":[{"award-number":["21200592"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore\u2019s open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6\/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development.<\/jats:p>","DOI":"10.1073\/pnas.2507707123","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:44:56Z","timestamp":1769535896000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1300-0009","authenticated-orcid":false,"given":"Naileth","family":"Gonzalez-Sanabria","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago","place":["Chicago"]},{"name":"Centro Interdisciplinario de Neurociencia de Valparaiso, Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valpara\u00edso Pasaje","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo F.","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5439-0225","authenticated-orcid":false,"given":"Maximiliano","family":"Rojas","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-7540","authenticated-orcid":false,"given":"Yorley","family":"Duarte","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-3575","authenticated-orcid":false,"given":"Fernando D.","family":"Gonzalez-Nilo","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7132-2793","authenticated-orcid":false,"given":"Eduardo","family":"Perozo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6044-5795","authenticated-orcid":false,"given":"Ramon","family":"Latorre","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valparaiso, Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valpara\u00edso Pasaje","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043407"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00001.2016"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/35038011"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI21388"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz314"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.130553"},{"key":"e_1_3_4_7_2","first-page":"1","article-title":"Role of BK channels in hypertension and potassium secretion","volume":"23","author":"Holtzclaw D.","year":"2014","unstructured":"D. Holtzclaw, R. Grimm, S. Sansom, Role of BK channels in hypertension and potassium secretion. Bone 23, 1\u20137 (2014).","journal-title":"Bone"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00118.2006"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","unstructured":"C. S. Bailey H. J. Moldenhauer S. M. Park S. Keros A. L. Meredith KCNMA1-linked channelopathy. J. Gen. Physiol. 151 1173\u20131189 (2019).","DOI":"10.1085\/jgp.201912457"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00495.2010"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2010.09935.x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12143"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12059"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)90442-1"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00389"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.06.028"},{"key":"e_1_3_4_17_2","article-title":"Inhalation of the BKCa-opener NS1619 attenuates right ventricular pressure and improves oxygenation in the rat monocrotaline model of pulmonary hypertension","volume":"35","author":"Revermann M.","year":"2014","unstructured":"M. Revermann , Inhalation of the BKCa-opener NS1619 attenuates right ventricular pressure and improves oxygenation in the rat monocrotaline model of pulmonary hypertension. FASEB J. 35, e21212 (2014).","journal-title":"FASEB J."},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2014.03.060"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.12.005"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920008117"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1114321109"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51409"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.20028605"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/BFb0030498"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.109.1.27"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.114.2.277"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq5772"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400555112"},{"key":"e_1_3_4_29_2","volume-title":"Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers","author":"Hoshi T.","year":"2016","unstructured":"T. Hoshi, S. H. Heinemann, Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers (Elsevier Inc., ed. 1, 2016), vol. 128.","edition":"1"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912506"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(92)07009-D"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1152\/advan.00006.2002"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.612713"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200409236"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.2408420"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.448118"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1727"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04152-4"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318006551"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318002425"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_3_4_45_2","unstructured":"N. Gonzalez-Sanabria G. F. Contreras R. Latorre E. Perozo Cryo-EM structure of the human BK channel bound to the agonist NS1619. Electron Microscopy Data Bank. https:\/\/www.ebi.ac.uk\/emdb\/EMD-75024. Deposited 8 January 2026."},{"key":"e_1_3_4_46_2","unstructured":"N. Gonzalez-Sanabria G. F. Contreras R. Latorre E. Perozo Cryo-EM structure of the human BK channel bound to the agonist NS1619. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/10AD. Deposited 8 January 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2507707123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:45:17Z","timestamp":1769535917000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2507707123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,2,3]]}},"alternative-id":["10.1073\/pnas.2507707123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2507707123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"2025-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2507707123"}}