3VI2
Crystal Structure Analysis of Plasmodium falciparum OMP Decarboxylase in complex with inhibitor HMOA
Summary for 3VI2
| Entry DOI | 10.2210/pdb3vi2/pdb |
| Descriptor | Orotidine 5'-phosphate decarboxylase, 4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic acid, SODIUM ION, ... (4 entities in total) |
| Functional Keywords | orotidine 5 f-monophosphate decarboxylase, lyase-lyase inhibitor complex, lyase/lyase inhibitor |
| Biological source | Plasmodium falciparum |
| Total number of polymer chains | 2 |
| Total formula weight | 76249.88 |
| Authors | Takashima, Y.,Mizohata, E.,Krungkrai, S.R.,Matsumura, H.,Krungkrai, J.,Horii, T.,Inoue, T. (deposition date: 2011-09-16, release date: 2012-08-01, Last modification date: 2024-03-20) |
| Primary citation | Takashima, Y.,Mizohata, E.,Krungkrai, S.R.,Fukunishi, Y.,Kinoshita, T.,Sakata, T.,Matsumura, H.,Krungkrai, J.,Horii, T.,Inoue, T. The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase J.Biochem., 152:133-138, 2012 Cited by PubMed Abstract: Orotidine 5'-monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) catalyses the final step in the de novo synthesis of uridine 5'-monophosphate (UMP) from orotidine 5'-monophosphate (OMP). A defective PfOMPDC enzyme is lethal to the parasite. Novel in silico screening methods were performed to select 14 inhibitors against PfOMPDC, with a high hit rate of 9%. X-ray structure analysis of PfOMPDC in complex with one of the inhibitors, 4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic acid, was carried out to at 2.1 Å resolution. The crystal structure revealed that the inhibitor molecule occupied a part of the active site that overlaps with the phosphate-binding region in the OMP- or UMP-bound complexes. Space occupied by the pyrimidine and ribose rings of OMP or UMP was not occupied by this inhibitor. The carboxyl group of the inhibitor caused a dramatic movement of the L1 and L2 loops that play a role in the recognition of the substrate and product molecules. Combining part of the inhibitor molecule with moieties of the pyrimidine and ribose rings of OMP and UMP represents a suitable avenue for further development of anti-malarial drugs. PubMed: 22740703DOI: 10.1093/jb/mvs070 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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