Re‐refinement of Plasmodium falciparum orotidine 5′‐monophosphate decarboxylase provides a clearer picture of an important malarial drug target

• Published in: Acta crystallographica. Section F, Structural biology communications Structural biology communications, 2018-10, Vol.74 (10), p.664-668
• Main Authors: Novak, Walter R. P., West, Korbin H. J., Kirkman, Lucy M. D., Brandt, Gabriel S.
• Format: Article
• Language: English
• Subjects: Antimalarials - chemistry; Binding Sites; Crystallization; Drug development; Electron density; Enzymes; Erythrocytes; Ligands; Michaelis complex; Models, Molecular; orotidine 5′‐monophosphate decarboxylase; Orotidine-5'-Phosphate Decarboxylase - chemistry; Orotidine-5'-Phosphate Decarboxylase - metabolism; Plasmodium falciparum; Plasmodium falciparum - chemistry; Plasmodium falciparum - enzymology; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Public health; Research Communications; re‐refinement; Substrate Specificity; Substrates; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - chemistry; Uridine Monophosphate - metabolism
• ISSN: 2053-230X; 2053-230X
• DOI: 10.1107/S2053230X18010610

The development of antimalarial drugs remains a public health priority, and the orotidine 5′‐monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) has great potential as a drug target. The crystallization of PfOMPDC with substrate bound represents an important advance for structure‐based drug‐design efforts [Tokuoka et al. (2008), J. Biochem.143, 69–78]. The complex of the enzyme bound to the substrate OMP (PDB entry 2za1) would be of particular utility in this regard. However, re‐refinement of this structure of the Michaelis complex shows that the bound ligand is the product rather than the substrate. Here, the re‐refinement of a set of three structures, the apo enzyme and two versions of the product‐bound form (PDB entries 2za1, 2za2 and 2za3), is reported. The improved geometry and fit of these structures to the observed electron density will enhance their utility in antimalarial drug design. In order to facilitate structure‐based drug‐design efforts, a set of structures of orotidine 5′‐monophosphate decarboxylase from the malaria parasite P. falciparum were re‐refined. This refitting greatly improves the global statistics of all three structures and shows that adding the substrate orotidine 5′‐monophosphate to the enzyme (PDB entry 2za1) generates a complex with the product UMP, rather than the substrate OMP as initially interpreted.