title: Disrupting the Allosteric Interaction between the Plasmodium falciparum cAMP-dependent Kinase and Its Regulatory Subunit.
abstract: The 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 signaling, we solved the structure of the PKA regulatory subunit in complex with cAMP and a related analogue that displays antimalarial activity, (Sp)-2-Cl-cAMPS. Prior to signaling, PKA-R holds the kinase's catalytic subunit (C) in an inactive state by exerting an allosteric inhibitory effect. When two cAMP molecules bind to PKA-R, they stabilize a structural conformation that facilitates its dissociation, freeing PKA-C to phosphorylate downstream substrates such as apical membrane antigen 1. Although PKA activity was known to be necessary for erythrocytic proliferation, we show that uncontrolled induction of PKA activity using membrane-permeable agonists is equally disruptive to growth.
authors.affiliation: From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and.
authors.forename: Dene R
authors.initials: DR
authors.lastname: Littler
authors.affiliation: the Burnet Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Bullen
authors.affiliation: the Burnet Institute, Melbourne, Victoria 3004, Australia.|the Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Harvey
authors.affiliation: the Centre for AgriBioscience, La Trobe University, Bundoora, Victoria 3086, Australia, and.
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.affiliation: From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and.|the Burnet Institute, Melbourne, Victoria 3004, Australia.|the Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and.|the Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN Wales, United Kingdom.|ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and paul.gilson@burnet.edu.au.|the Burnet Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
mesh_terms: D000494:Allosteric Regulation; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000737:chemistry; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: cyclic AMP (cAMP); malaria; plasmodium; protein kinase A (PKA); protein structure