A5070515091- Malaria Research and Control
- Phosphodiesterase function and regulation
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Adenosine and Purinergic Signaling
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Drug-Induced Hepatotoxicity and Protection
- Synthesis and Catalytic Reactions
- Historical Influence and Diplomacy
- Cancer, Stress, Anesthesia, and Immune Response
- Traditional and Medicinal Uses of Annonaceae
- Biochemical and Molecular Research
- Advanced biosensing and bioanalysis techniques
- German Literature and Culture Studies
- Bioactive Compounds and Antitumor Agents
- Click Chemistry and Applications
- European Political History Analysis
- Trypanosoma species research and implications
- Signaling Pathways in Disease
- Computational Drug Discovery Methods
Biaffin (Germany)
2020
University of Kassel
2013-2017
Hesse (Germany)
2015
A-kinase anchoring proteins (AKAPs) play an important role in the spatial and temporal regulation of protein kinase A (PKA) by scaffolding critical intracellular signaling complexes. Here we report design conformationally constrained peptides that disrupt interactions between PKA AKAPs isoform-selective manner. Peptides derived from Kinase Binding (AKB) domain several were chemically modified to contain all-hydrocarbon staple target docking/dimerization PKA-R, thereby occluding AKAP...
A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora diverse pathways, their cellular roles are often elusive due to the dynamic nature these complexes. can interact with type I or II PKA holoenzymes virtue high-affinity interactions R-subunits. As means delineate AKAP-mediated cells, we sought develop isoform-selective disruptors AKAP signaling....
Most malaria deaths are caused by the protozoan parasite Plasmodium falciparum Its life cycle is regulated a cGMP-dependent protein kinase (PfPKG), whose inhibition promising antimalaria strategy. Allosteric inhibitors, such as cGMP analogs, offer enhanced selectivity relative to competitive inhibitors. However, mechanisms underlying allosteric PfPKG incompletely understood. Here, we show that 8-NBD-cGMP an effective antagonist. Using comparative NMR analyses of key regulatory domain, PfD,...
The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is a key regulator across the malaria parasite life cycle. Little known about PfPKG's activation mechanism. Here we report that carboxyl cyclic nucleotide binding domain functions as "gatekeeper" for by providing highest cGMP affinity and selectivity. To understand mechanism, have solved its crystal structures with without at 2.0 1.9 Å, respectively. These revealed PfPKG-specific capping triad forms upon binding, disrupting...
cGMP-dependent protein kinase from Plasmodium falciparum ( PfPKG) plays a crucial role in the sexual as well asexual proliferation of this human malaria causing parasite. However, function and regulation PfPKG are largely unknown. Previous studies showed that domain organization significantly differs PKG hPKG) indicated critical cyclic nucleotide binding D (CNB-D). We identified novel mechanism, where CNB-D controls activation parasite specific kinase. Here, activity is not dependent on...
Cyclic GMP analogs, 8-Br, 8-pCPT, and PET-cGMP, have been widely used for characterizing cellular functions of cGMP-dependent protein kinase (PKG) I II isotypes. However, interpreting results obtained using these analogs has difficult due to their low isotype specificity. Additionally, each two binding sites with different cGMP affinities analog selectivities, making understanding the molecular basis specificity compounds even more challenging. To determine structural basis, we generated...
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Isoform-Selective Disruption of AKAP-Localized PKA Using Hydrocarbon Stapled PeptidesYuxiao Wang, Tienhuei G. Ho, Daniela Bertinetti, Matthias Neddermann, Eugen Franz, Gary C. H. Mo, Lewis P. Schendowich, Avinash Sukhu, Raybun Spelts, Jin Zhang, Friedrich W. Herberg, and Eileen J. Kennedy*Cite this: ACS Chem. Biol. 2014, 9, 6, 1386Publication Date (Web):May 2014Publication History...
Background Plasmodium falciparum cGMP-dependent protein kinase (pfPKG) is a validated therapeutic target of malaria. As key regulator its life cycle, pfPKG plays crucial role in both the sexual and asexual blood-stages that cause malaria pathology. Inhibiting blocks proliferation transmission parasite [1,2]. However development pfPKG-specific inhibitor has been greatly hampered by lack high-resolution structure information to guide drug design. Targeting ATP binding site an approach commonly...
BackgroundcAMP-dependent protein kinase (PKA) and cGMP-dependent (PKG) are the main effectors ofdistinct cyclic nucleotide pathways preferentiallyactivated by cAMP or cGMP, respectively.We recently characterized isolated C-terminal cyc-lic binding domain (CNB-B) of humanPKG Ib as highly cGMP-selective (manuscript in pre-paration). In a crystal structure CNB-B two novelcGMP-specific interaction sites were identified addi-tion to previously described threonine residue (T317)in phosphate...
Background Malaria is one of the most dangerous tropical diseases worldwide, resulting in approximately 1.5-2.7 million deaths per year [1]. Furthermore, malaria belongs to four major infectious also including HIV, tuberculosis and hepatitis. In humans, transmitted by species genus Plasmodium. However, are caused Plasmodium falciparum [2]. The cGMP-dependent protein kinase (PfPKG) key regulators parasite life cycle both sexual asexual blood-stages. Inhibition PfPKG stops differentiation...