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The 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.