BPS2026 – Structural basis for the subtype-selective activation of KCa3.1 channels

Intermediate-conductance Ca 2+ -activated K + (K Ca 3.1) channels are gated by a Ca 2+ -calmodulin dependent mechanism. K Ca 3.1 activators may be useful in enhancing T cell cytotoxicity in cancer treatment, improving coronary artery blood flow, and preventing platelet aggregation. We report cryo-electron microscopy structures of K Ca 3.1 and the closely related K Ca 2.2 channels bound with SKA-31 and SKA-111, respectively. SKA-31 and SKA-111 share a binding pocket at the interface between both channels’ S 45 A helix and calmodulin. SKA-111 exhibits ∼70-fold selectivity in contrast to the ∼7.3-fold selectivity of SKA-31 for K Ca 3.1 over K Ca 2.2. The different conformations of calmodulin in the two channel structures may underlie the subtype-selectivity for K Ca 3.1. The calmodulin helix IV is positioned outward, forming a larger pocket between the calmodulin N-lobe and the S 45 A helix of K Ca 3.1 compared to the K Ca 2.2 structure. Therefore, SKA-31 and SKA-111 fit into calmodulin’s N-lobe in K Ca 3.1 with higher binding energy than in K Ca 2.2. The bulkier SKA-111 better exploits the differences between the binding pockets of these two channels, which explains its much-improved selectivity for K Ca 3.1 than SKA-31.