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K2.2通道激活剂亚型选择性的结构基础。

Structural basis for the subtype-selectivity of K2.2 channel activators.

作者信息

Zhang Miao, Nam Young-Woo, Ramanishka Alena, Xu Yang, Yasuda Rose Marie, Im Dohyun, Cui Meng, Chandy George, Wulff Heike

机构信息

Chapman University.

SLAC National Accelerator Laboratory.

出版信息

Res Sq. 2025 May 16:rs.3.rs-6568445. doi: 10.21203/rs.3.rs-6568445/v1.

DOI:10.21203/rs.3.rs-6568445/v1
PMID:40470184
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12136229/
Abstract

Small-conductance (K2.2) and intermediate-conductance (K3.1) Ca-activated K channels are gated by a Ca-calmodulin dependent mechanism. NS309 potentiates the activity of both K2.2 and K3.1, while rimtuzalcap selectively activates K2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of K2.2 channels bound with NS309 and rimtuzalcap, in addition to K3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K2.2. Calmodulin's N-lobes in the K2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin's Nlobes in the K3.1 structure are closer to each other and are constrained by the HC helices of K3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting K2.2 channels.

摘要

小电导（K2.2）和中电导（K3.1）钙激活钾通道由钙调蛋白依赖性机制门控。NS309增强K2.2和K3.1的活性，而利姆图扎尔卡普选择性激活K2.2。利姆图扎尔卡普已用于治疗脊髓小脑共济失调和特发性震颤的临床试验。我们报告了与NS309和利姆图扎尔卡普结合的K2.2通道以及与NS309结合的K3.1通道的冷冻电镜结构。两个通道中钙调蛋白和细胞质HC螺旋的不同构象是利姆图扎尔卡普对K2.2亚型选择性的基础。K2.2结构中钙调蛋白的N叶相距很远，并发生构象变化以容纳NS309或利姆图扎尔卡普。K3.1结构中钙调蛋白的N叶彼此更靠近，并受到K3.1的HC螺旋的限制，这允许NS309结合，但不允许体积更大的利姆图扎尔卡普结合。这些结构为靶向K2.2通道的基于结构的药物设计提供了框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/ca7fd5d45faa/nihpp-rs6568445v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/7b83d6b03ad1/nihpp-rs6568445v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/6a2ab6e25f96/nihpp-rs6568445v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/e5b398a2bb46/nihpp-rs6568445v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/e1621e531774/nihpp-rs6568445v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/80a77713521e/nihpp-rs6568445v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/659967b308f9/nihpp-rs6568445v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/ca7fd5d45faa/nihpp-rs6568445v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/7b83d6b03ad1/nihpp-rs6568445v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/6a2ab6e25f96/nihpp-rs6568445v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/e5b398a2bb46/nihpp-rs6568445v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/e1621e531774/nihpp-rs6568445v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/80a77713521e/nihpp-rs6568445v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/659967b308f9/nihpp-rs6568445v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/109c/12136229/ca7fd5d45faa/nihpp-rs6568445v1-f0007.jpg

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