Calcium-gated potassium channel blockade via membrane-facing fenestrations.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
31 Aug 2023
31 Aug 2023
Historique:
received:
04
06
2021
accepted:
18
07
2023
medline:
1
9
2023
pubmed:
1
9
2023
entrez:
31
8
2023
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 37653172
doi: 10.1038/s41589-023-01406-2
pii: 10.1038/s41589-023-01406-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : 088352
Organisme : Medical Advances Without Animals Trust (MAWA)
ID : N/A
Organisme : Medical Advances Without Animals Trust (MAWA)
ID : N/A
Organisme : Department of Education and Training | Australian Research Council (ARC)
ID : DP210102405
Organisme : Department of Education and Training | Australian Research Council (ARC)
ID : DP2201035501
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP1141974
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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