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Title | Calcium-gated potassium channel blockade via membrane-facing fenestrations. |
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Journal, issue, pages | Nat Chem Biol, Vol. 20, Issue 1, Page 52-61, Year 2024 |
Publish date | Aug 31, 2023 |
Authors | Chen Fan / Emelie Flood / Nattakan Sukomon / Shubhangi Agarwal / Toby W Allen / Crina M Nimigean / |
PubMed 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 ...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. |
External links | Nat Chem Biol / PubMed:37653172 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.88 - 3.5 Å |
Structure data | EMDB-27459, PDB-8djb: EMDB-29605, PDB-8fz7: EMDB-9405, PDB-5bki: |
Chemicals | ChemComp-CD: ChemComp-PGW: ChemComp-K: ChemComp-HOH: ChemComp-YQ1: ChemComp-YQ4: |
Source |
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Keywords | TRANSPORT PROTEIN / ion channel / MTHK / MEMBRANE PROTEIN / Blocker TpeA |