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-Structure paper
タイトル | Calcium-gated potassium channel blockade via membrane-facing fenestrations. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 20, Issue 1, Page 52-61, Year 2024 |
掲載日 | 2023年8月31日 |
著者 | Chen Fan / Emelie Flood / Nattakan Sukomon / Shubhangi Agarwal / Toby W Allen / Crina M Nimigean / |
PubMed 要旨 | 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. |
リンク | Nat Chem Biol / PubMed:37653172 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.88 - 3.5 Å |
構造データ | EMDB-27459, PDB-8djb: EMDB-29605, PDB-8fz7: |
化合物 | ChemComp-CD: ChemComp-PGW: ChemComp-K: ChemComp-HOH: ChemComp-YQ1: ChemComp-YQ4: |
由来 |
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キーワード | TRANSPORT PROTEIN / ion channel / MTHK / MEMBRANE PROTEIN / Blocker TpeA |