Structural Basis for the Subtype-Selective Activation of K_Ca3.1 Channels

Authors

• Alena Ramanishka, Chapman University
• Joshua A. Nasburg, University of California, Davis
• Yang Xu, Stanford University
• Xinyi Ma, Northeastern University
• Reza Mehvar, Chapman UniversityFollow
• Meng Cui, Northeastern UniversityFollow
• Young-Woo Nam, Chapman UniversityFollow
• Heike Wulff, University of California, Davis
• Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

5-14-2026

Abstract

The intermediate-conductance (K_Ca3.1) and the small-conductance (K_Ca2.2) Ca²⁺-activated K⁺ channels share a Ca²⁺-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K_Ca3.1 and K_Ca2.2 in complex with two benzothiazole-type activators. While SKA-31 is only moderately selective (∼7.3-fold), its derivative SKA-111 exhibits ∼70-fold selectivity for K_Ca3.1 over K_Ca2.2. SKA-31 and SKA-111 both bind in a pocket at the interface between the S₄₅A helix and calmodulin where they allosterically modulate the inner gate of the two channels. SKA-31 binds with comparable energies in the two channels, consistent with its moderate selectivity for K_Ca3.1 over K_Ca2.2. In the K_Ca3.1 structure, the calmodulin helix IV is positioned outward, forming a pocket that more readily accommodates the bulkier SKA-111 that sits deeper inside calmodulin’s N-lobe in K_Ca3.1 than in K_Ca2.2. The resulting higher binding energy explains the improved selectivity of SKA-111 for K_Ca3.1 compared to the less selective SKA-31.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Journal. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Structure, volume 34, issue 7, in 2026. https://doi.org/10.1016/j.str.2026.04.010

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Recommended Citation

Ramanishka A, Nasburg JA, Xu Y, et al. Structural basis for the subtype-selective activation of KCa3.1 channels. Structure. 2026;34(7):1040-1049.e3. https://doi.org/10.1016/j.str.2026.04.010

Copyright

Elsevier

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.