Structural highlights
FunctionMTHK_METTH Calcium-gated potassium channel. Publication Abstract from PubMedQuaternary 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. Calcium-gated potassium channel blockade via membrane-facing fenestrations.,Fan C, Flood E, Sukomon N, Agarwal S, Allen TW, Nimigean CM Nat Chem Biol. 2024 Jan;20(1):52-61. doi: 10.1038/s41589-023-01406-2. Epub 2023 , Aug 31. PMID:37653172[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
This page was last modified 05:52, 14 May 2025.