6FQX

Plasmodium falciparum 6-phosphogluconate dehydrogenase in its apo form, in complex with its cofactor NADP+ and in complex with its substrate 6-phosphogluconate

6FQX の概要

• エントリーDOI: 10.2210/pdb6fqx/pdb
• 関連するPDBエントリー: 6FQY 6FQZ
• 分子名称: 6-phosphogluconate dehydrogenase, decarboxylating, GLYCEROL, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: plasmodium, complex, substrate, redoxregulation, oxidoreductase
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 427125.92

構造登録者

Fritz-Wolf, K.,Haeussler, K.,Reichmann, M.,Rahlfs, S.,Becker, K. (登録日: 2018-02-15, 公開日: 2018-08-22, 最終更新日: 2024-01-17)

主引用文献

Haeussler, K.,Fritz-Wolf, K.,Reichmann, M.,Rahlfs, S.,Becker, K.
Characterization of Plasmodium falciparum 6-Phosphogluconate Dehydrogenase as an Antimalarial Drug Target.
J. Mol. Biol., 430:4049-4067, 2018

PubMed Abstract: The enzyme 6-phosphogluconate dehydrogenase (6PGD) of the malaria parasite Plasmodium falciparum catalyzes the third step of the pentose phosphate pathway converting 6-phosphogluconate (6PG) to ribulose 5-phosphate. The NADPH produced by 6PGD is crucial for antioxidant defense and redox regulation, and ribose 5-phosphate is essential for DNA and RNA synthesis in the rapidly growing parasite. Thus, 6PGD represents an attractive antimalarial drug target. In this study, we present the X-ray structures of Pf6PGD in native form as well as in complex with 6PG or nicotinamide adenine dinucleotide phosphate (NADP) at resolutions of 2.8, 1.9, and 2.9 Å, respectively. The overall structure of the protein is similar to structures of 6PGDs from other species; however, a flexible loop close to the active site rearranges upon binding of 6PG and likely regulates the conformation of the cofactor NADP. Upon binding of 6PG, the active site loop adopts a closed conformation. In the absence of 6PG, the loop opens and NADP is bound in a waiting position, indicating that the cofactor and 6PG bind independently from each other. This sequential binding mechanism was supported by kinetic studies on the homodimeric wild-type Pf6PGD. Furthermore, the function of the Plasmodium-specific residue W104L mutant was characterized by site-directed mutagenesis. Notably, the activity of Pf6PGD was found to be post-translationally redox regulated via S-nitrosylation, and screening the Medicines for Malaria Venture Malaria Box identified several compounds with ICs in the low micromolar range. Together with the three-dimensional structure of the protein, this is a promising starting point for further drug discovery approaches.

PubMed: 30098336
DOI: 10.1016/j.jmb.2018.07.030

実験手法

X-RAY DIFFRACTION (2.8 Å)