Structural highlights
Publication Abstract from PubMedThe ubiquitous second messenger cAMP mediates signal transduction processes in the malarial parasite that regulate host erythrocyte invasion and the proliferation of merozoites. In Plasmodium falciparum the central receptor for cAMP is the single regulatory subunit (R) of Protein kinase A (PKA). To aid the development of compounds that can selectively dysregulate parasite PKA signalling we solved the structure of the PKA regulatory subunit in complex with cAMP and a related analog that displays antimalarial activity: Sp-2Cl-cAMPS. Prior to signalling, PKA-R holds the kinases catalytic subunit (C) in an inactive state by exerting an allosteric inhibitory affect. When two cAMP molecules bind to PKA-R they stabilise a structural conformation that facilitates its dissociation, freeing PKA-C to phosphorylate down-stream substrates such as Apical Membrane Antigen 1. We show that untimely induction of this response with membrane permeable Sp-2Cl-cAMPS blocks parasite proliferation via a PKA-R dependent mechanism. Disrupting the allosteric interaction between the Plasmodium falciparum cAMP-dependent kinase and its regulatory subunit.,Littler DR, Bullen HE, Harvey KL, Beddoe T, Crabb BS, Rossjohn J, Gilson PR J Biol Chem. 2016 Oct 13. pii: jbc.M116.750174. PMID:27738107[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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