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Structural basis for the subtype-selectivity of KCa2.2 channel activators
Young-Woo Nam1,2, Alena Ramanishka1,2, Yang Xu3
1Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA.
Nature Communications
|January 8, 2026
Summary
Cryo-EM structures reveal how NS309 and rimtuzalcap bind to calcium-activated potassium channels (KCa2.2 and KCa3.1). These findings explain rimtuzalcap
Area of Science:
- Biophysics
- Molecular Biology
- Pharmacology
Background:
- Small-conductance (KCa2.2) and intermediate-conductance (KCa3.1) calcium-activated potassium channels are crucial drug targets.
- These channels are regulated by calcium and calmodulin, influencing cellular excitability.
- Modulators like NS309 and rimtuzalcap exhibit differential effects on KCa2.2 and KCa3.1.
Purpose of the Study:
- To elucidate the structural basis for the subtype-selectivity of rimtuzalcap towards KCa2.2 channels.
- To understand the molecular mechanisms underlying the potentiation of KCa2.2 and KCa3.1 by NS309.
- To provide a structural foundation for developing novel KCa2.2-targeting therapeutics.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
- Structural analysis of KCa2.2 and KCa3.1 channels bound to NS309 and rimtuzalcap.
- Investigation of a KCa3.1 mutant (R355K) to assess drug binding.
Main Results:
- Determined cryo-EM structures of NS309-bound KCa2.2/KCa3.1 and rimtuzalcap-bound KCa2.2.
- Identified distinct calmodulin and cytoplasmic helix conformations responsible for rimtuzalcap's KCa2.2 selectivity.
- Revealed NS309 binds to pre-formed pockets, while rimtuzalcap utilizes an induced-fit mechanism in KCa2.2.
- Demonstrated that a KCa3.1_R355K mutation enables rimtuzalcap binding.
Conclusions:
- The structural differences in calmodulin and HC helices dictate rimtuzalcap's selective KCa2.2 activation.
- NS309 exhibits broader binding capabilities due to its interaction with pre-existing pockets.
- These structures offer a blueprint for structure-based drug design targeting KCa2.2 channels for neurological disorders.
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