1.A.1.5.35
The cyclic ABP-gated K⁺ channel, SthK of 430 aas and 6 TMSs in a 2 + 2 + 1 + P-loop +1 TMS arrangement. This channel and others have been studied by high-speed atomic force microscopy (HS-AFM) which has made it possible to characterized the conformational dynamics of single unlabeled transmembrane channels and transporters (Heath and Scheuring 2019). The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels and inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. SthK shares features with CNG and HCN channels and is a model for this channel family. Thon et al. 2024 showed that SthK activity is inhibited by PIP2. A cryo-EM structure of SthK in nanodiscs revealed a PIP2-fitting density coordinated by arginine and lysine residues from the S4 helix and the C-linker, located between voltage-sensing and pore domains of adjacent subunits. Mutation of two arginine residues weakened PIP2 inhibition with the double mutant displaying insensitivity to PIP2.