Peter Man-Un Ung

Highlights • Virtual screening with a GIRK alcohol pocket reveals a GIRK1-selective activator • GiGA1 activates the GIRK channel directly without G proteins • Natively expressed GIRK channels in the hippocampus are activated by GiGA1 • Systemic GiGA1 application reduces seizures in a convulsant animal model Summary G-protein-gated inwardly rectifying K+ (GIRK) channels are essential effectors of inhibitory neurotransmission in the brain.

Shraga et al. use covalent docking to identify covalent inhibitors for MKK7. Crystallography validated the predicted binding pose, and optimization led to potent inhibitors that block JNK (MKK7's substrate) phosphorylation in cells. The compounds are selective and as such can serve as tools to further study MKK7.

Protein kinases are dynamic, adopting different conformational states that are critical for their catalytic activity. We assess a range of structural features derived from the conserved αC helix and DFG motif to define the conformational space of the catalytic domain of protein kinases. We then construct Kinformation, a random forest classifier, to annotate the conformation of 3,708 kinase structures in the PDB.