# Structural basis for the subtype-selectivity of KCa2.2 channel activators

## TL;DR

This paper explains how certain drugs selectively activate specific potassium channels based on structural differences revealed by cryo-EM.

## Contribution

The study reveals structural mechanisms behind subtype-selectivity of KCa2.2 channel activators using cryo-EM.

## Key findings

- Structural differences in calmodulin and HC helices explain rimtuzalcap's selectivity for KCa2.2.
- N-lobes of calmodulin in KCa2.2 are flexible, allowing binding of both NS309 and rimtuzalcap.
- N-lobes in KCa3.1 are constrained, preventing rimtuzalcap binding.

## Abstract

Small-conductance (KCa2.2) and intermediate-conductance (KCa3.1) Ca2+-activated K+ channels are gated by a Ca2+-calmodulin dependent mechanism. NS309 potentiates the activity of both KCa2.2 and KCa3.1, while rimtuzalcap selectively activates KCa2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of KCa2.2 channels bound with NS309 and rimtuzalcap, in addition to KCa3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for KCa2.2. Calmodulin’s N-lobes in the KCa2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin’s Nlobes in the KCa3.1 structure are closer to each other and are constrained by the HC helices of KCa3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting KCa2.2 channels.