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<p>Small-conductance (K<sub>Ca</sub>2.2) and intermediate-conductance (K<sub>Ca</sub>3.1) Ca<sup>2+</sup>-activated K<sup>+</sup> channels are gated by a Ca<sup>2+</sup>-calmodulin dependent mechanism. NS309 potentiates the activity of both K<sub>Ca</sub>2.2 and K<sub>Ca</sub>3.1, while rimtuzalcap selectively activates K<sub>Ca</sub>2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound K<sub>Ca</sub>2.2 and K<sub>Ca</sub>3.1, in addition to structures of rimtuzalcap-bound K<sub>Ca</sub>2.2 and mutant K<sub>Ca</sub>3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K<sub>Ca</sub>2.2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in K<sub>Ca</sub>2.2 requiring conformational changes. In K<sub>Ca</sub>2.2, calmodulin’s N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In K<sub>Ca</sub>3.1, calmodulin’s N-lobes are closer to each other and constrained by K<sub>Ca</sub>3.1’s HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in K<sub>Ca</sub>3.1’s HB helix with lysine (K<sub>Ca</sub>3.1_R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting K<sub>Ca</sub>2.2 channels.</p>

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Structural basis for the subtype-selectivity of KCa2.2 channel activators

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Young-Woo Nam,
  • Alena Ramanishka,
  • Yang Xu,
  • Rose Marie Haynes Yasuda,
  • Joshua A. Nasburg,
  • Dohyun Im,
  • Meng Cui,
  • K. George Chandy,
  • Heike Wulff,
  • Miao Zhang

摘要

Small-conductance (KCa2.2) and intermediate-conductance (KCa3.1) Ca2+-activated K+ channels are gated by a Ca2+-calmodulin dependent mechanism. NS309 potentiates the activity of both KCa2.2 and KCa3.1, while rimtuzalcap selectively activates KCa2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound KCa2.2 and KCa3.1, in addition to structures of rimtuzalcap-bound KCa2.2 and mutant KCa3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for KCa2.2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in KCa2.2 requiring conformational changes. In KCa2.2, calmodulin’s N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In KCa3.1, calmodulin’s N-lobes are closer to each other and constrained by KCa3.1’s HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in KCa3.1’s HB helix with lysine (KCa3.1_R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting KCa2.2 channels.