3ELC

Crystal structure of 2C-methyl-D-erythritol 2,4-clycodiphosphate synthase complexed with ligand

3ELC の概要

• エントリーDOI: 10.2210/pdb3elc/pdb
• 分子名称: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-pyrimidin-2-one, ... (5 entities in total)
• 機能のキーワード: mecdp-synthase, isoprene biosynthesis, lyase, magnesium, manganese, metal-binding
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 54022.88

構造登録者

Hunter, W.N.,Ramsden, N.L.,Ulaganathan, V. (登録日: 2008-09-22, 公開日: 2009-08-25, 最終更新日: 2023-11-01)

主引用文献

Ramsden, N.L.,Buetow, L.,Dawson, A.,Kemp, L.A.,Ulaganathan, V.,Brenk, R.,Klebe, G.,Hunter, W.N.
A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy
J.Med.Chem., 52:2531-2542, 2009

PubMed Abstract: The nonmevalonate route to isoprenoid biosynthesis is essential in Gram-negative bacteria and apicomplexan parasites. The enzymes of this pathway are absent from mammals, contributing to their appeal as chemotherapeutic targets. One enzyme, 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), has been validated as a target by genetic approaches in bacteria. Virtual screening against Escherichia coli IspF (EcIspF) was performed by combining a hierarchical filtering methodology with molecular docking. Docked compounds were inspected and 10 selected for experimental validation. A surface plasmon resonance assay was developed and two weak ligands identified. Crystal structures of EcIspF complexes were determined to support rational ligand development. Cytosine analogues and Zn(2+)-binding moieties were characterized. One of the putative Zn(2+)-binding compounds gave the lowest measured K(D) to date (1.92 +/- 0.18 muM). These data provide a framework for the development of IspF inhibitors to generate lead compounds of therapeutic potential against microbial pathogens.

PubMed: 19320487
DOI: 10.1021/jm801475n

実験手法

X-RAY DIFFRACTION (2.5 Å)