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Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.
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•The active site of PknG preferentially interacts with extended peptide substrates•PknG domains flanking the kinase core define substrate selectivity•A rubredoxin-like metal-binding domain downregulates PknG kinase activity•A K181-E198 salt bridge is not required for PknG kinase activity
In this work, Lisa and colleagues investigate the molecular determinants of enzyme activity, substrate specificity, and regulation of the protein kinase PknG from Mycobacterium tuberculosis, providing alternatives for the design of selective inhibitors with potential therapeutic applications.