Cryo-EM structures of the small-conductance Ca2+-activated KCa2.2 channel

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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Small-conductance Ca2+-activated K+ (KCa2.1-KCa2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the KCa2.2 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 KCa2.x channels.

Date: 2025
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DOI: 10.1038/s41467-025-59061-1

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