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Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition.

Holton S, Merckx A, Burgess D, Doerig C, Noble M, Endicott J
Structure 11 1329-37 (2003)
Related entries: 1v0b, 1v0o, 1v0p

Cited: 49 times
EuropePMC logo PMID: 14604523

Abstract

Plasmodium falciparum cell cycle regulators are promising targets for antimalarial drug design. We have determined the structure of PfPK5, the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. The fold and the mechanism of inactivation of monomeric CDKs are highly conserved across evolution. ATP-competitive CDK inhibitors have been developed as potential leads for cancer therapeutics. These studies have identified regions of the CDK active site that can be exploited to achieve significant gains in inhibitor potency and selectivity. We have cocrystallized PfPK5 with three inhibitors that target such regions. The sequence differences between PfPK5 and human CDKs within these inhibitor binding sites suggest that selective inhibition is an attainable goal. Such compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for antimalarial drug development.

Reviews - 1ob3 mentioned but not cited (3)

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Articles - 1ob3 mentioned but not cited (3)

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Reviews citing this publication (15)

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Articles citing this publication (28)

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  4. Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period. Vougogiannopoulou K, Ferandin Y, Bettayeb K, Myrianthopoulos V, Lozach O, Fan Y, Johnson CH, Magiatis P, Skaltsounis AL, Mikros E, Meijer L. J Med Chem 51 6421-6431 (2008)
  5. 7-Bromoindirubin-3'-oxime induces caspase-independent cell death. Ribas J, Bettayeb K, Ferandin Y, Knockaert M, Garrofé-Ochoa X, Totzke F, Schächtele C, Mester J, Polychronopoulos P, Magiatis P, Skaltsounis AL, Boix J, Meijer L. Oncogene 25 6304-6318 (2006)
  6. Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined. Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, Bischler N, Skaltsounis AL, Zographos SE, Oikonomakos NG. Proteins 79 703-719 (2011)
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  11. The Malaria Parasite Cyclin H Homolog PfCyc1 Is Required for Efficient Cytokinesis in Blood-Stage Plasmodium falciparum. Robbins JA, Absalon S, Streva VA, Dvorin JD. mBio 8 e00605-17 (2017)
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  16. Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites. Carrasco MP, Machado M, Gonçalves L, Sharma M, Gut J, Lukens AK, Wirth DF, André V, Duarte MT, Guedes RC, Dos Santos DJ, Rosenthal PJ, Mazitschek R, Prudêncio M, Moreira R. ChemMedChem 11 2194-2204 (2016)
  17. Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds. Engels K, Beyer C, Suárez Fernández ML, Bender F, Gassel M, Unden G, Marhöfer RJ, Mottram JC, Selzer PM. ChemMedChem 5 1259-1271 (2010)
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  19. Comparative insight into nucleotide excision repair components of Plasmodium falciparum. Tajedin L, Anwar M, Gupta D, Tuteja R. DNA Repair (Amst) 28 60-72 (2015)
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  21. Antimalarial activity of kinase inhibitor, nilotinib, in vitro and in vivo. Ishiyama A, Iwatsuki M, Hokari R, Sawa M, Ōmura S, Otoguro K. J Antibiot (Tokyo) 68 469-472 (2015)
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  23. Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones. Lande DH, Nasereddin A, Alder A, Gilberger TW, Dzikowski R, Grünefeld J, Kunick C. Molecules 26 4739 (2021)
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  25. Comment Can mosquitoes be bitten? A new hope for anti-malarial drug design. Brinen LS, Stout TJ. Structure 11 1309-1310 (2003)
  26. Effects of cyclin-dependent kinase inhibitor Purvalanol B application on protein expression and developmental progression in intra-erythrocytic Plasmodium falciparum parasites. Bullard KM, Broccardo C, Keenan SM. Malar J 14 147 (2015)
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