4Y67

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC176, and manganese

4Y67 の概要

• エントリーDOI: 10.2210/pdb4y67/pdb
• 分子名称: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast, [(2R)-2-{2-[hydroxy(methyl)amino]-2-oxoethyl}-5-phenylpentyl]phosphonic acid, MANGANESE (II) ION, ... (4 entities in total)
• 機能のキーワード: enzyme-inhibitor complex, mep pathway, isoprenoid biosynthesis, oxidoreductase
• 由来する生物種: Plasmodium falciparum
• 細胞内の位置: Plastid, apicoplast : Q8IKG4
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97069.43

構造登録者

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (登録日: 2015-02-12, 公開日: 2015-04-01, 最終更新日: 2024-01-10)

主引用文献

Chofor, R.,Sooriyaarachchi, S.,Risseeuw, M.D.,Bergfors, T.,Pouyez, J.,Johny, C.,Haymond, A.,Everaert, A.,Dowd, C.S.,Maes, L.,Coenye, T.,Alex, A.,Couch, R.D.,Jones, T.A.,Wouters, J.,Mowbray, S.L.,Van Calenbergh, S.
Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.
J.Med.Chem., 58:2988-3001, 2015

PubMed Abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

PubMed: 25781377
DOI: 10.1021/jm5014264

実験手法

X-RAY DIFFRACTION (1.6 Å)