Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition.
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.
Holton
Simon
S
Laboratory of Molecular Biophysics, Department of Biochemistry, South Parks Road, OX1 3QU, Oxford, United Kingdom.
Merckx
Anais
A
Burgess
Darren
D
Doerig
Christian
C
Noble
Martin
M
Endicott
Jane
J
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D018360:Crystallography, X-Ray; D016213:Cyclins / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D015800:Protozoan Proteins / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry; D013696:Temperature
D016213:Cyclins; D004791:Enzyme Inhibitors; D007211:Indoles; C406811:PfPK5 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D013451:Sulfonic Acids; C437986:indirubin-5-sulfonic acid