Characteristics of the Plasmodium falciparum PK5 ATP-binding site: implications for the design of novel antimalarial agents.
Increasing worldwide resistance of Plasmodium falciparum (P. falciparum) to traditional chemotherapy strategies such as chloroquine and mefloquine demonstrates the urgent need for the discovery of novel chemotherapeutic agents in the fight against malaria. The recent discovery of P. falciparum Protein Kinase 5 (PfPK5) invites the possibility of selectively targeting the life cycle of P. falciparum in order to prevent cerebral malaria. PfPK5 bears a high degree of sequence identity (>58%) to a structurally conserved family of mammalian kinases known as the cyclin-dependent kinases (CDKs). The CDKs are the key regulatory elements governing the ordered progression of the mammalian cell cycle. With numerous X-ray crystal structures of CDK2 to provide a structural template, here we present a three-dimensional structural model of PfPK5 constructed using computer-based homology modeling techniques. Our model was used to compare the ATP binding site of PfPK5 with that of the mammalian kinase CDK2. Furthermore, kinase-ligand interactions of PfPK5 with known inhibitors were investigated and compared to available crystal structures of CDK2 with inhibitors bound. The focus of the study is to identify similarities and differences between the ATP binding sites of the two kinases that can be exploited for future rational drug design.
Keenan
Susan M
SM
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Welsh
William J
WJ
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D016779:Malaria, Cerebral / Q000517:prevention & control; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000962:Antimalarials; D008024:Ligands; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D018844:Cyclin-Dependent Kinases