Structural basis for the subtype-selective activation of KCa3.1 channels
Abstract
The intermediate-conductance (KCa3.1) and the small-conductance (KCa2.2) Ca2+-activated K+ channels share a Ca2+-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of KCa3.1 and KCa2.2 in complex with two benzothiazole-type activators. While SKA-31 is only moderately selective (∼7.3-fold), its derivative SKA-111 exhibits ∼70-fold selectivity for KCa3.1 over KCa2.2. SKA-31 and SKA-111 both bind in a pocket at the interface between the S45A 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 KCa3.1 over KCa2.2. In the KCa3.1 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 KCa3.1 than in KCa2.2. The resulting higher binding energy explains the improved selectivity of SKA-111 for KCa3.1 compared to the less selective SKA-31.
Read the paper
Related studies
- A Survey on Knowledge Graphs: Representation, Acquisition, and Applications
- Toxicity of nanomaterials
- The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies
- Halogen bonding (X‐bonding): A biological perspective
- Biofilm formation at the air–liquid interface by the Pseudomonas fluorescens SBW25 wrinkly spreader requires an acetylated form of cellulose
- Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.