3C8N

Crystal structure of apo-FGD1 from Mycobacterium tuberculosis

3C8N の概要

• エントリーDOI: 10.2210/pdb3c8n/pdb
• 関連するPDBエントリー: 3B4Y
• 分子名称: Probable F420-dependent glucose-6-phosphate dehydrogenase FGD1 (2 entities in total)
• 機能のキーワード: tim barrel, non-prolyl cis-peptide, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 158760.50

構造登録者

Bashiri, G.,Squire, C.J.,Moreland, N.J.,Baker, E.N. (登録日: 2008-02-12, 公開日: 2008-04-22, 最終更新日: 2021-10-20)

主引用文献

Bashiri, G.,Squire, C.J.,Moreland, N.J.,Baker, E.N.
Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding.
J.Biol.Chem., 283:17531-17541, 2008

PubMed Abstract: The modified flavin coenzyme F(420) is found in a restricted number of microorganisms. It is widely distributed in mycobacteria, however, where it is important in energy metabolism, and in Mycobacterium tuberculosis (Mtb) is implicated in redox processes related to non-replicating persistence. In Mtb, the F(420)-dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F(420) for the in vivo activation of the nitroimidazopyran prodrug PA-824, currently being developed for anti-tuberculosis therapy against both replicating and persistent bacteria. The structure of M. tuberculosis FGD1 has been determined by x-ray crystallography both in its apo state and in complex with F(420) and citrate at resolutions of 1.90 and 1.95 A(,) respectively. The structure reveals a highly specific F(420) binding mode, which is shared with several other F(420)-dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F(420) and is shown to be a competitive inhibitor (IC(50) 43 microm). Modeling of the binding of the glucose 6-phosphate (G6P) substrate identifies a positively charged phosphate binding pocket and shows that G6P, like citrate, packs against the isoalloxazine moiety of F(420) and helps promote a butterfly bend conformation that facilitates F(420) reduction and catalysis.

PubMed: 18434308
DOI: 10.1074/jbc.M801854200

実験手法

X-RAY DIFFRACTION (1.9 Å)