Structural basis for the subtype-selectivity of K(Ca)2.2 channel activators.

Small-conductance (K(Ca)2.2) and intermediate-conductance (K(Ca)3.1) Ca(2+)-activated K(+) channels are gated by a Ca(2+)-calmodulin dependent mechanism. NS309 potentiates the activity of both K(Ca)2.2 and K(Ca)3.1, while rimtuzalcap selectively activates K(Ca)2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of K(Ca)2.2 channels bound with NS309 and rimtuzalcap, in addition to K(Ca)3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K(Ca)2.2. Calmodulin's N-lobes in the K(Ca)2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin's Nlobes in the K(Ca)3.1 structure are closer to each other and are constrained by the HC helices of K(Ca)3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting K(Ca)2.2 channels.