Keep a lid on it: A troika in kinase allostery

The malaria parasite Plasmodium falciparum encodes a cGMP-dependent protein kinase G (PfPKG) that is critical for its life cycle. Specific cGMP analogs are able to act as partial agonists of PfPKG. Using the exquisite diagnostic power of NMR chemical shifts, Byun et al. demonstrate that the extent of agonism by these cGMP derivatives relates to the degree of stabilization of a unique inactive conformation that shares structural features with both the ligand-free, inactive and the cGMP-bound, active states. The observation of this third state helps to generalize a novel paradigm for the allosteric activation of kinase function and may open opportunities for the development of novel therapeutics.