2V2V

IspE in complex with ligand

Summary for 2V2V

• Entry DOI: 10.2210/pdb2v2v/pdb
• Related: 2V2Q 2V2Z 2V34 2V8P 2VF3
• Descriptor: 4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL KINASE, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: transferase, 4-diphosphocytidyl-2c-methyl-d- erythritol, aquifex aeolicus, nucleotide-binding, isoprene biosynthesis, kinase, atp-binding, non-mevalonate
• Biological source: AQUIFEX AEOLICUS
• Total number of polymer chains: 2
• Total formula weight: 62397.36

Authors

Alphey, M.S.,Hunter, W.N. (deposition date: 2007-06-07, release date: 2007-06-19, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)