2V2V

IspE in complex with ligand

2V2V の概要

• エントリーDOI: 10.2210/pdb2v2v/pdb
• 関連するPDBエントリー: 2V2Q 2V2Z 2V34 2V8P 2VF3
• 分子名称: 4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL KINASE, SULFATE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: transferase, 4-diphosphocytidyl-2c-methyl-d- erythritol, aquifex aeolicus, nucleotide-binding, isoprene biosynthesis, kinase, atp-binding, non-mevalonate
• 由来する生物種: AQUIFEX AEOLICUS
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62397.36

構造登録者

Alphey, M.S.,Hunter, W.N. (登録日: 2007-06-07, 公開日: 2007-06-19, 最終更新日: 2024-05-08)

主引用文献

Crane, C.M.,Hirsch, A.K.,Alphey, M.S.,Sgraja, T.,Lauw, S.,Illarionova, V.,Rohdich, F.,Eisenreich, W.,Hunter, W.N.,Bacher, A.,Diederich, F.
Synthesis and Characterization of Cytidine Derivatives that Inhibit the Kinase Ispe of the Non-Mevalonate Pathway for Isoprenoid Biosynthesis.
Chemmedchem, 3:91-, 2008

PubMed Abstract: The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for the development of novel drugs against malaria and tuberculosis. This pathway is used exclusively by the corresponding pathogens, but not by humans. A series of water-soluble, cytidine-based inhibitors that were originally designed for the fourth enzyme in the pathway, IspD, were shown to inhibit the subsequent enzyme, the kinase IspE (from Escherichia coli). The binding mode of the inhibitors was verified by co-crystal structure analysis, using Aquifex aeolicus IspE. The crystal structures represent the first reported example of a co-crystal structure of IspE with a synthetic ligand and confirmed that ligand binding affinity originates mainly from the interactions of the nucleobase moiety in the cytidine binding pocket of the enzyme. In contrast, the appended benzimidazole moieties of the ligands adopt various orientations in the active site and establish only poor intermolecular contacts with the protein. Defined binding sites for sulfate ions and glycerol molecules, components in the crystallization buffer, near the well-conserved ATP-binding Gly-rich loop of IspE were observed. The crystal structures of A. aeolicus IspE nicely complement the one from E. coli IspE for use in structure-based design, namely by providing invaluable structural information for the design of inhibitors targeting IspE from Mycobacterium tuberculosis and Plasmodium falciparum. Similar to the enzymes from these pathogens, A. aeolicus IspE directs the OH group of a tyrosine residue into a pocket in the active site. In the E. coli enzyme, on the other hand, this pocket is lined by phenylalanine and has a more pronounced hydrophobic character.

PubMed: 18033714
DOI: 10.1002/CMDC.200700208

実験手法

X-RAY DIFFRACTION (2.4 Å)