Divergent Allostery Reveals Critical Differences between Structurally Homologous Regulatory Domains of Plasmodium Falciparum and Human Protein Kinase G

Malaria is a life-threatening infectious disease primarily caused by the Plasmodium falciparum parasite. The increasing resistance to current antimalarial drugs and their side effects has led to an urgent need for novel malaria drug targets, such as the P. falciparum cGMP-dependent protein kinase (pfPKG). However, PKG plays an essential regulatory role also in the human host. Human PKG (hPKG) and pfPKG are controlled by structurally homologs cGMP-binding domains (CBDs). Here, we show that despite the structural similarities between the essential CBDs in pfPKG and hPKG, their respective allosteric networks differ significantly. Through comparative analyses of CHESCA, molecular dynamics simulations, and backbone internal dynamics measurements, we found that conserved allosteric elements within the essential CBDs are wired differently in pfPKG and hPKG to implement cGMP-dependent kinase activation. Such pfPKG vs. hPKG rewiring of allosteric networks was unexpected due to the structural similarity between the two essential CBDs. Yet, such finding provides crucial information on which elements to target for selective inhibition of pfPKG vs. hPKG, which may potentially reduce undesired side-effects in malaria treatments.