Abstract
The small-conductance calcium-activated potassium (SK1-3 or KCa2) channels regulate the intrinsic excitability and firing frequency of excitable cells. SK channels are modulated by a variety of distinct modulators; however, the underlying mechanisms remain elusive. Here, we present four cryoelectron microscopy structures of the human SK2-calmodulin complex bound with apamin, UCL1684, AP30663, and CAD-1883, elucidating their distinct binding sites and regulatory mechanisms. Apamin and UCL1684 compete for a similar binding site above the selectivity filter, which is formed by the distinct S3-S4 linker of SK2. CAD-1883 glues the N-lobe of calmodulin and the S4-S5 linker of SK2, reinforcing the open state. In contrast, AP30663 resides in the central cavity of SK2, blocking ion conductance. This study reveals multiple modulation sites in SK2 and the molecular mechanisms for the inhibition and potentiation of SK channels, which could advance rational drug design targeting SK2 channel for the treatment of cardiovascular and neurological disorders.
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Data availability
The cryo-EM density maps of human SK2-apamin, SK2-UCL1684, SK2-CAD-1883, and SK2-AP30663 have been deposited into the Electron Microscopy Data Bank (EMDB) under accession codes EMD-65357, EMD-65359, EMD-65358, and EMD-65356, respectively. The coordinates of human SK2-apamin, SK2-UCL1684, SK2-CAD, and SK2-AP have been deposited into the Protein Data Bank (PDB) under accession codes 9VUA, 9VUC, 9VUB, and 9VU9, respectively. Previously published data for the structures used in this study are available with PDB accession codes: SK4, 6CNO, 6CNM, and 6CNN; apamin, 7OXF; Shaker Kv channel, 7SJ1; rat SK2, 8V2H and 8V3G; human SK2-4 chimera, 9O52. The source data underlying Figs. 2–4 and Supplementary Figs. 1, 7, 9, and 10 are provided as a Source Data file. Source data are provided with this paper.
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Acknowledgments
We thank Dr. B. Xu at the Cryo-EM Center of the School of Advanced Agricultural Sciences of Peking University and D. Sun at the Cryo-EM Facility at the Institute of Physics, Chinese Academy of Science & Beijing Branch of Songshan Lake Materials Laboratory for support in cryo-EM data collection. We thank Dr. Lu Ma and Wei Fan for their research assistance service. This work is funded by the National Natural Science Foundation of China (32222034 and U25A2080 to W.Z.; 32271272 and T2221001 to D.J.; 82430048 and 82125010 to B.P.), the Natural Science Foundation of Jiangxi Province (20252BAC230007 to W.Z.; 20242BAB24003 to B.P.), and the Taishan Scholars Program (tsqnz20231243 to C.C.). This work is also supported by the Medical-Engineering Interdisciplinary Talent Development Program and the Fund of the School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University.
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D.J., W.Z., and B.P. conceived and designed the experiments. B.M. prepared samples for the cryo-EM study and made all the constructs. D.W., B.M., Z.X., and C.C. collected the cryo-EM data. D.W. and D.J. processed the data and built and refined the models. E.C. and Z.W. performed the electrophysiology experiments. B.M. and D.W. prepared the figures. B.M., D.W., E.C., C.C., L.S., B.P., W.Z., and D.J. analysed and interpreted the results. D.J. and D.W. wrote the paper, and all the authors reviewed and revised the paper.
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Ma, B., Wu, D., Cao, E. et al. Structural mechanisms for inhibition and activation of human small-conductance Ca2+-activated potassium channel SK2. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68475-4
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DOI: https://doi.org/10.1038/s41467-026-68475-4
