5MRM

Arabidopsis thaliana IspD in complex with Isoxazole (4)

5MRM の概要

• エントリーDOI: 10.2210/pdb5mrm/pdb
• 関連するPDBエントリー: 1W77 2YC5 4NAK
• 分子名称: 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, chloroplastic, 2,4-bis(bromanyl)-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (7 entities in total)
• 機能のキーワード: herbicide, anti-infectives, drug discovery, allosteric inhibition, transferase
• 由来する生物種: Arabidopsis thaliana (Mouse-ear cress)
• 細胞内の位置: Plastid, chloroplast stroma : P69834
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26413.76

構造登録者

Schwab, A.,Illarionov, B.,Frank, A.,Kunfermann, A.,Seet, M.,Bacher, A.,Witschel, M.,Fischer, M.,Groll, M.,Diederich, F. (登録日: 2016-12-23, 公開日: 2017-07-19, 最終更新日: 2024-01-17)

主引用文献

Schwab, A.,Illarionov, B.,Frank, A.,Kunfermann, A.,Seet, M.,Bacher, A.,Witschel, M.C.,Fischer, M.,Groll, M.,Diederich, F.
Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands.
ACS Chem. Biol., 12:2132-2138, 2017

PubMed Abstract: Enzymes of the nonmevalonate pathway of isoprenoid biosynthesis are attractive targets for the development of herbicides and drugs against infectious diseases. While this pathway is essential for many pathogens and plants, mammals do not depend on it for the synthesis of isoprenoids. IspD, the third enzyme of the nonmevalonate pathway, is unique in that it has an allosteric regulatory site. We elucidated the binding mode of phenylisoxazoles, a new class of allosteric inhibitors. Allosteric inhibition is effected by large conformational changes of a loop region proximal to the active site. We investigated the different roles of residues in this loop by mutation studies and identified repulsive interactions with Asp291 and Asp292 to be responsible for inhibition. Crystallographic data and the response of mutant enzymes to three different classes of allosteric inhibitors provide an in-depth understanding of the allosteric mechanism. The obtained mutant enzymes show selective resistance to allosteric inhibitors and provide conceptually valuable information for future engineering of herbicide-resistant crops. We found that the isoprenoid precursors IPP and DMAPP are natural inhibitors of Arabidopsis thaliana IspD; however, they do not seem to bind to the allosteric site.

PubMed: 28686408
DOI: 10.1021/acschembio.7b00004

実験手法

X-RAY DIFFRACTION (1.8 Å)