5K8S

cAMP bound PfPKA-R (297-441)

Summary for 5K8S

• Entry DOI: 10.2210/pdb5k8s/pdb
• Related: 5KBF
• Descriptor: CAMP-dependent protein kinase regulatory subunit, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (3 entities in total)
• Functional Keywords: plasmodium falciparum, pka, protein kinase a, camp, cbd, cyclic nucleotide binding, cnb, regulatory domain, r, transferase
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 2
• Total formula weight: 34385.17

Authors

Littler, D.R.,Gilson, P.R.,Crabb, B.S.,Rossjohn, J.J. (deposition date: 2016-05-31, release date: 2016-10-12, Last modification date: 2023-09-27)

Primary citation

Littler, D.R.,Bullen, H.E.,Harvey, K.L.,Beddoe, T.,Crabb, B.S.,Rossjohn, J.,Gilson, P.R.
Disrupting the Allosteric Interaction between the Plasmodium falciparum cAMP-dependent Kinase and Its Regulatory Subunit.
J. Biol. Chem., 291:25375-25386, 2016

PubMed 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, (S)-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.

PubMed: 27738107
DOI: 10.1074/jbc.M116.750174

Experimental method

X-RAY DIFFRACTION (1.15 Å)