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PDBsum entry 2v2q

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2v2q
Jmol
Contents
Protein chains
269 a.a. *
Ligands
GOL ×2
NVG ×2
SO4 ×5
Metals
_BR ×7
Waters ×347
* Residue conservation analysis
PDB id:
2v2q
Name: Transferase
Title: Ispe in complex with ligand
Structure: 4-diphosphocytidyl-2-c-methyl-d-erythritol kinase. Chain: a, b. Synonym: cmk, 4-(cytidine-5'-diphospho)-2-c-methyl-d- erythritol kinase. Engineered: yes
Source: Aquifex aeolicus. Organism_taxid: 63363. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.212     R-free:   0.234
Authors: M.S.Alphey,W.N.Hunter
Key ref: C.M.Crane et al. (2008). Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis. ChemMedChem, 3, 91. PubMed id: 18033714
Date:
06-Jun-07     Release date:   19-Jun-07    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
O67060  (ISPE_AQUAE) -  4-diphosphocytidyl-2-C-methyl-D-erythritol kinase
Seq:
Struc:
268 a.a.
269 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.1.148  - 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol = ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
ATP
+ 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
= ADP
+ 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
      Cofactor: Mn(2+) or Mg(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     isoprenoid biosynthetic process   4 terms 
  Biochemical function     nucleotide binding     5 terms  

 

 
    reference    
 
 
ChemMedChem 3:91 (2008)
PubMed id: 18033714  
 
 
Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis.
C.M.Crane, A.K.Hirsch, M.S.Alphey, T.Sgraja, S.Lauw, V.Illarionova, F.Rohdich, W.Eisenreich, W.N.Hunter, A.Bacher, F.Diederich.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20208151 J.Kalinowska-Tłuścik, L.Miallau, M.Gabrielsen, G.A.Leonard, S.M.McSweeney, and W.N.Hunter (2010).
A triclinic crystal form of Escherichia coli 4-diphosphocytidyl-2C-methyl-D-erythritol kinase and reassessment of the quaternary structure.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 66, 237-241.
PDB code: 2ww4
18793870 H.Eoh, P.J.Brennan, and D.C.Crick (2009).
The Mycobacterium tuberculosis MEP (2C-methyl-d-erythritol 4-phosphate) pathway as a new drug target.
  Tuberculosis (Edinb), 89, 1.  
18633530 A.K.Hirsch, M.S.Alphey, S.Lauw, M.Seet, L.Barandun, W.Eisenreich, F.Rohdich, W.N.Hunter, A.Bacher, and F.Diederich (2008).
Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis.
  Org Biomol Chem, 6, 2719-2730.
PDB code: 2vf3
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.