Effects of Aqueous-Organic Solvent Systems on Crystals and the Structure of the DNA Polymerase from the apicoplast of Plasmodium falciparum

Malaria in humans, primarily caused by the parasite Plasmodium falciparum, is a mosquito-borne disease causing 450,000 deaths annually. Parasites emerging in central Africa, India, southeast Asia, and northern South America exhibit increasing resistance to antimalarial drugs. Malaria vaccines under development have yet to provide broad protection to vulnerable populations. Hence new, potent antimalarial drugs will likely play a central role in the control and eventual eradication of the disease. Plasmodium falciparum contains a plastid called the apicoplast. The apicoplast is absent in humans but necessary for parasite survival. Substances that poison the essential functions of the apicoplast, could serve as drugs for the treatment of malaria. The DNA polymerase of the apicoplast (apPOL) governs an essential function (DNA synthesis in support of apicoplast reproduction) and is a target of drug screening efforts. In order to use the current crystal form of the polymerase in drug screens, structures in the presence of several aqueous-organic solvent systems serve as controls, allowing the investigator to separate the effects of a bound inhibitor from the effects of the solvent system needed to solubilize the inhibitor. Presented here are crystal structures of apPOL in solvent systems containing dimethyl sulfoxide, 2-methyl-2,4-pentandiol and acetonitrile