{"entity": "publication", "iuid": "2e109b479efc44a88a051a343eaba0b6", "timestamp": "2026-08-22T07:47:41.242Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/2e109b479efc44a88a051a343eaba0b6.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/2e109b479efc44a88a051a343eaba0b6"}}, "title": "Calcium-gated potassium channel blockade via membrane-facing fenestrations.", "authors": [{"family": "Fan", "given": "Chen", "initials": "C"}, {"family": "Flood", "given": "Emelie", "initials": "E", "orcid": "0000-0002-1981-9636", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bf975e0fdbe440108a20df1637a61dab.json"}}, {"family": "Sukomon", "given": "Nattakan", "initials": "N", "orcid": "0000-0002-8443-9533", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ffb428dec00a41cd84667092cc27bdf8.json"}}, {"family": "Agarwal", "given": "Shubhangi", "initials": "S"}, {"family": "Allen", "given": "Toby W", "initials": "TW", "orcid": "0000-0002-3521-7950", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f3792457d97f42adaee2c2563a218ea2.json"}}, {"family": "Nimigean", "given": "Crina M", "initials": "CM", "orcid": "0000-0002-6254-4447", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7e75571e2b98464ca45504dabe307081.json"}}], "type": "journal article", "published": "2024-01-00", "journal": {"title": "Nat. Chem. Biol.", "issn": "1552-4469", "volume": "20", "issue": "1", "pages": "52-61", "issn-l": "1552-4450"}, "abstract": "Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.", "doi": "10.1038/s41589-023-01406-2", "pmid": "37653172", "labels": [], "xrefs": [{"db": "mid", "key": "NIHMS1935574"}, {"db": "pmc", "key": "PMC10847966"}, {"db": "pii", "key": "10.1038/s41589-023-01406-2"}, {"db": "PDB", "key": "8FZ7"}, {"db": "PDB", "key": "5BKI"}, {"db": "PDB", "key": "5BKJ"}, {"db": "PDB", "key": "5BKK"}, {"db": "PDB", "key": "8DJB"}], "notes": [], "created": "2026-08-21T11:51:59.896Z", "modified": "2026-08-21T11:52:00.082Z"}