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<p>Small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (K<sub>Ca</sub>2.1-K<sub>Ca</sub>2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K<sub>Ca</sub>2.2 channel in complex with calmodulin and Ca<sup>2+</sup>, alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter’s GYG signature by 180°, causing the outer selectivity filter to widen and water to enter the filter. Disruption of the tether by a mutation narrows the outer selectivity filter, realigns Tyr362 to the position seen in other K<sup>+</sup> channels, and significantly increases unitary conductance. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of K<sub>Ca</sub>2.x channels.</p>

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Cryo-EM structures of the small-conductance Ca2+-activated KCa2.2 channel

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月17日

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  • Young-Woo Nam,
  • Dohyun Im,
  • Ana Santa Cruz Garcia,
  • Marios L. Tringides,
  • Hai Minh Nguyen,
  • Yan Liu,
  • Razan Orfali,
  • Alena Ramanishka,
  • Grigore Pintilie,
  • Chih-Chia Su,
  • Meng Cui,
  • Diomedes E. Logothetis,
  • Edward W. Yu,
  • Heike Wulff,
  • K. George Chandy,
  • Miao Zhang

摘要

Small-conductance Ca2+-activated K+ (KCa2.1-KCa2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the KCa2.2 channel in complex with calmodulin and Ca2+, alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter’s GYG signature by 180°, causing the outer selectivity filter to widen and water to enter the filter. Disruption of the tether by a mutation narrows the outer selectivity filter, realigns Tyr362 to the position seen in other K+ channels, and significantly increases unitary conductance. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of KCa2.x channels.