Structural highlights
FunctionKCNN2_HUMAN Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin. Publication Abstract from PubMedThe intermediate-conductance (K(Ca)3.1) and the small-conductance (K(Ca)2.2) Ca(2+)-activated K(+) channels share a Ca(2+)-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K(Ca)3.1 and K(Ca)2.2 in complex with two benzothiazole-type activators. While SKA-31 is only moderately selective ( approximately 7.3-fold), its derivative SKA-111 exhibits approximately 70-fold selectivity for K(Ca)3.1 over K(Ca)2.2. SKA-31 and SKA-111 both bind in a pocket at the interface between the S(45)A 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(Ca)3.1 over K(Ca)2.2. In the K(Ca)3.1 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(Ca)3.1 than in K(Ca)2.2. The resulting higher binding energy explains the improved selectivity of SKA-111 for K(Ca)3.1 compared to the less selective SKA-31. Structural basis for the subtype-selective activation of K(Ca)3.1 channels.,Ramanishka A, Nasburg JA, Xu Y, Ma X, Mehvar R, Cui M, Nam YW, Wulff H, Zhang M Structure. 2026 May 14:S0969-2126(26)00116-4. doi: 10.1016/j.str.2026.04.010. PMID:42140186[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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