3A06

Crystal structure of DXR from Thermooga maritia, in complex with fosmidomycin and NADPH

3A06 の概要

• エントリーDOI: 10.2210/pdb3a06/pdb
• 分子名称: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-[FORMYL(HYDROXY)AMINO]PROPYLPHOSPHONIC ACID, ... (5 entities in total)
• 機能のキーワード: reductoisomerase, mep pathway, isoprene biosynthesis, metal-binding, nadp, oxidoreductase
• 由来する生物種: Thermotoga maritima
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 87168.93

構造登録者

Takenoya, M.,Ohtaki, A.,Noguchi, K.,Sasaki, Y.,Ohsawa, K.,Yohda, M.,Yajima, S. (登録日: 2009-03-02, 公開日: 2010-03-16, 最終更新日: 2024-03-13)

主引用文献

Takenoya, M.,Ohtaki, A.,Noguchi, K.,Endo, K.,Sasaki, Y.,Ohsawa, K.,Yajima, S.,Yohda, M.
Crystal structure of 1-deoxy-d-xylulose 5-phosphate reductoisomerase from the hyperthermophile Thermotoga maritima for insights into the coordination of conformational changes and an inhibitor binding
J.Struct.Biol., 170:532-539, 2010

PubMed Abstract: Isopentenyl diphosphate is a precursor of various isoprenoids and is produced by the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway in plastids of plants, protozoa and many eubacteria. A key enzyme in the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), has been shown to be the target of fosmidomycin, which works as an antimalarial, antibacterial and herbicidal compound. In this paper, we report studies of kinetics and the crystal structures of the thermostable DXR from the hyperthermophile Thermotoga maritima. Unlike the mesophilic DXRs, Thermotoga DXR (tDXR) showed activity only with Mg(2+) at its growth temperature. We solved the crystal structures of tDXR with and without fosmidomycin. The structure without fosmidomycin but unexpectedly bound with 2-methyl-2,4-pentanediol (MPD), revealing a new extra space available for potential drug design. This structure adopted the closed form by rigid domain rotation but without the flexible loop over the active site, which was considered as a novel conformation. Further, the conserved Asp residue responsible for cation binding seemed to play an important role in adjusting the position of fosmidomycin. Taken together, our kinetic and the crystal structures illustrate the binding mode of fosmidomycin that leads to its slow, tight binding according to the conformational changes of DXR.

PubMed: 20353826
DOI: 10.1016/j.jsb.2010.03.015

実験手法

X-RAY DIFFRACTION (2 Å)