Cryo-EM Structures of the Small-conductance Ca²⁺-activated K_Ca2.2 Channel

Authors

Young-Woo Nam, Chapman UniversityFollow
Dohyun Im, Kyoto University
Ana Santa Cruz Garcia, Northeastern University
Marios L. Tringides, Case Western Reserve University
Hai Minh Nguyen, University of California, Davis
Yan Liu, Stanford University
Razan Orfali, Chapman UniversityFollow
Alena Ramanishka, Chapman University
Grigore Pintilie, Stanford University
Chih-Chia Su, Case Western Reserve University
Meng Cui, Northeastern University
Diomedes E. Logothetis, Northeastern University
Edward W. Yu, Case Western Reserve University
Heike Wulff, University of California, Davis
K. George Chandy, Nanyang Technological University, Singapore
Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

4-17-2025

Abstract

Small-conductance Ca²⁺-activated K+ (K_Ca2.1-K_Ca2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K_Ca2.2 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 K_Ca2.x channels.

Comments

This article was originally published in Nature Communications, volume 16, in 2025. https://doi.org/10.1038/s41467-025-59061-1

Recommended Citation

Nam YW, Im D, Garcia ASC, et al. Cryo-EM structures of the small-conductance Ca²⁺-activated K_Ca2.2 channel. Nat Commun. 2025;16(1):3690. https://doi.org/10.1038/s41467-025-59061-1

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The authors

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