5JC1

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, LC55 and manganese

5JC1 の概要

• エントリーDOI: 10.2210/pdb5jc1/pdb
• 分子名称: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic, [(2R)-2-{2-[hydroxy(methyl)amino]-2-oxoethyl}-5-(3-methoxyphenyl)pentyl]phosphonic acid, MANGANESE (II) ION, ... (6 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 (isolate 3D7)
• 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: 98430.90

構造登録者

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (登録日: 2016-04-14, 公開日: 2016-08-24, 最終更新日: 2024-01-10)

主引用文献

Sooriyaarachchi, S.,Chofor, R.,Risseeuw, M.D.,Bergfors, T.,Pouyez, J.,Dowd, C.S.,Maes, L.,Wouters, J.,Jones, T.A.,Van Calenbergh, S.,Mowbray, S.L.
Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with beta-Arylpropyl Analogues of Fosmidomycin.
Chemmedchem, 11:2024-2036, 2016

PubMed Abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

PubMed: 27487410
DOI: 10.1002/cmdc.201600249

実験手法

X-RAY DIFFRACTION (1.65 Å)