Dynamical Basis of Allosteric Activation for the Plasmodium falciparum Protein Kinase G

2021 ◽  
Author(s):  
Jinfeng Huang ◽  
Jung Ah Byun ◽  
Bryan VanSchouwen ◽  
Philipp Henning ◽  
Friedrich W. Herberg ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Allosteric Activation ◽  
Falciparum Protein

scholarly journals Dynamical Basis of Allosteric Activation for the Plasmodium falciparum Protein Kinase G

2021 ◽  
Vol 120 (3) ◽  
pp. 298a
Author(s):  
Jinfeng Huang ◽  
Jung Ah Byun ◽  
Bryan VanSchouwen ◽  
Philipp Henning ◽  
Laura-Li Sarmiento Murga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Allosteric Activation ◽  
Falciparum Protein

scholarly journals Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG)

2018 ◽  
Vol 28 (19) ◽  
pp. 3168-3173 ◽  
Author(s):  
Denise J. Tsagris ◽  
Kristian Birchall ◽  
Nathalie Bouloc ◽  
Jonathan M. Large ◽  
Andy Merritt ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Selective Inhibitors ◽  
Falciparum Protein

Characterization of Plasmodium falciparum protein kinase 2

2008 ◽  
Vol 162 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Kentaro Kato ◽  
Atsushi Sudo ◽  
Kyousuke Kobayashi ◽  
Yukinobu Tohya ◽  
Hiroomi Akashi
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Falciparum Protein

Expression and biochemical characterization of the Plasmodium falciparum protein kinase A catalytic subunit

2009 ◽  
Vol 104 (6) ◽  
pp. 1299-1305 ◽  
Author(s):  
Nathalie Wurtz ◽  
Boris Pastorino ◽  
Lionel Almeras ◽  
Sébastien Briolant ◽  
Claude Villard ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Biochemical Characterization ◽  
Catalytic Subunit ◽  
Falciparum Protein ◽  
Kinase A

scholarly journals Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway

BMC Biology ◽  
2012 ◽  
Vol 10 (1) ◽  
pp. 5 ◽  
Author(s):  
Eeshita G Dastidar ◽  
Guillem Dayer ◽  
Zoe M Holland ◽  
Dominique Dorin-Semblat ◽  
Aurelie Claes ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase Ck2 ◽  
Chromatin Assembly ◽  
Assembly Pathway ◽  
Kinase Ck2 ◽  
Falciparum Protein

A Plasmodium falciparum protein kinase with two unusually large kinase inserts

1995 ◽  
Vol 72 (1-2) ◽  
pp. 163-178 ◽  
Author(s):  
Barbara Kappes ◽  
Jiewu Yang ◽  
Bernd W. Suetterlin ◽  
Klara Rathgeb-Szabo ◽  
Meinrad J. Lindt ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Falciparum Protein

scholarly journals Reduced Activity of Mutant Calcium-Dependent Protein Kinase 1 Is Compensated in Plasmodium falciparum through the Action of Protein Kinase G

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Abhisheka Bansal ◽  
Kayode K. Ojo ◽  
Jianbing Mu ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Wild Type ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Reduced Activity ◽  
Calcium Dependent Protein Kinase

ABSTRACT We used a sensitization approach that involves replacement of the gatekeeper residue in a protein kinase with one with a different side chain. The activity of the enzyme with a bulky gatekeeper residue, such as methionine, cannot be inhibited using bumped kinase inhibitors (BKIs). Here, we have used this approach to study Plasmodium falciparum calcium-dependent protein kinase 1 ( Pf CDPK1). The methionine gatekeeper substitution, T145M, although it led to a 47% reduction in transphosphorylation, was successfully introduced into the CDPK1 locus using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9. As methionine is a bulky residue, BKI 1294 had a 10-fold-greater effect in vitro on the wild-type enzyme than on the methionine mutant. However, in contrast to in vitro data with recombinant enzymes, BKI 1294 had a slightly greater inhibition of the growth of CDPK1 T145M parasites than the wild type. Moreover, the CDPK1 T145M parasites were more sensitive to the action of compound 2 (C2), a specific inhibitor of protein kinase G (PKG). These results suggest that a reduction in the activity of CDPK1 due to methionine substitution at the gatekeeper position is compensated through the direct action of PKG or of another kinase under the regulation of PKG. The transcript levels of CDPK5 and CDPK6 were significantly upregulated in the CDPK1 T145M parasites. The increase in CDPK6 or some other kinase may compensate for decrease in CDPK1 activity during invasion. This study suggests that targeting two kinases may be more effective in chemotherapy to treat malaria so as not to select for mutations in one of the enzymes. IMPORTANCE Protein kinases of Plasmodium falciparum are being actively pursued as drug targets to treat malaria. However, compensatory mechanisms may reverse the drug activity against a kinase. In this study, we show that replacement of the wild-type threonine gatekeeper residue with methionine reduces the transphosphorylation activity of CDPK1. Mutant parasites with methionine gatekeeper residue compensate the reduced activity of CDPK1 through the action of PKG possibly by upregulation of CDPK6 or some other kinase. This study highlights that targeting one enzyme may lead to changes in transcript expression of other kinases that compensate for its function and may select for mutants that are less dependent on the target enzyme activity. Thus, inhibiting two kinases is a better strategy to protect the antimalarial activity of each, similar to artemisinin combination therapy or malarone (atovaquone and proguanil).

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