3VI2

Crystal Structure Analysis of Plasmodium falciparum OMP Decarboxylase in complex with inhibitor HMOA

3VI2 の概要

• エントリーDOI: 10.2210/pdb3vi2/pdb
• 分子名称: Orotidine 5'-phosphate decarboxylase, 4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic acid, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: orotidine 5 f-monophosphate decarboxylase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Plasmodium falciparum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76249.88

構造登録者

Takashima, Y.,Mizohata, E.,Krungkrai, S.R.,Matsumura, H.,Krungkrai, J.,Horii, T.,Inoue, T. (登録日: 2011-09-16, 公開日: 2012-08-01, 最終更新日: 2024-03-20)

主引用文献

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

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: 22740703
DOI: 10.1093/jb/mvs070

実験手法

X-RAY DIFFRACTION (2.1 Å)