Figure 1. Activating PKA in mammals and trypanosomatid pathogens.

(A–D) Stick representations of the molecular structures of the cyclic nucleotide cAMP (A), and three purine nucleosides: adenosine (B), guanosine (C) and inosine (D). The main difference between these molecules is that cAMP contains a phosphate group which the purine nucleosides lack. In most organisms, an important kinase called PKA is activated when two cAMP molecules bind to two tandem binding sites in the regulatory subunit of the kinase (Su et al., 1995; Kim et al., 2007; Akimoto et al., 2015). In trypanosomatid pathogens, on the other hand, PKA is activated when purine nucleosides bind to these sites. (E) Ribbon/stick structures showing a purine nucleoside (inosine; yellow sticks) bound to T. brucei PKA at site A (grey ribbons), overlaid with cAMP (cyan sticks) bound to the same site for mammalian (Bos taurus) PKA (purple ribbons). (F) Ribbon/stick structures showing inosine and cAMP bound to PKA at site B. The amino acids that differ between mammalian and trypanosomatid PKA are labelled: Arg209 and Arg333 in mammalian PKA are replaced by Thr318 and Asn442 in trypanosomatid PKA, while Ala202 and Ala326 are replaced by Glu311 and Glu435. For clarity, other parts of the PKA structures have been omitted. The proposed clash between Glu311/Glu435 of trypanosomatid PKA and the phosphate group of cAMP that prevents cAMP from binding is also indicated (dashed ovals). PKA: protein kinase A; the protein structures used for PKA can be found at PDB ID 6FLO (T. brucei) and PDB ID 1RGS (B. taurus).