3I68

Plasmodium falciparum dihydroorotate dehydrogenase bound with triazolopyrimidine-based inhibitor DSM2

3I68 の概要

• エントリーDOI: 10.2210/pdb3i68/pdb
• 関連するPDBエントリー: 3I65 3I68
• 分子名称: Dihydroorotate dehydrogenase homolog, mitochondrial, N-anthracen-2-yl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: plasmodium falciparum, dihydroorotate dehydrogenase, triazolopyrimidine, inhibitor, dsm2, fad, flavoprotein, membrane, mitochondrion, mitochondrion inner membrane, oxidoreductase, pyrimidine biosynthesis, transit peptide
• 由来する生物種: Plasmodium falciparum 3D7
• 細胞内の位置: Mitochondrion inner membrane (By similarity); Single-pass membrane protein (Potential): Q08210
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47590.15

構造登録者

Deng, X.,Phillips, M.A. (登録日: 2009-07-06, 公開日: 2009-07-28, 最終更新日: 2023-09-06)

主引用文献

Deng, X.,Gujjar, R.,El Mazouni, F.,Kaminsky, W.,Malmquist, N.A.,Goldsmith, E.J.,Rathod, P.K.,Phillips, M.A.
Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds.
J.Biol.Chem., 284:26999-27009, 2009

PubMed Abstract: Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.

PubMed: 19640844
DOI: 10.1074/jbc.M109.028589

実験手法

X-RAY DIFFRACTION (2.4 Å)