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PDBsum entry 3elc
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* Residue conservation analysis
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PDB id:
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Lyase
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Title:
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Crystal structure of 2c-methyl-d-erythritol 2,4-clycodiphosphate synthase complexed with ligand
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Structure:
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2-c-methyl-d-erythritol 2,4-cyclodiphosphate synthase. Chain: a, b, c. Synonym: mecps, mecdp-synthase. Engineered: yes
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Source:
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Escherichia coli k-12. Organism_taxid: 83333. Strain: k12. Gene: ispf. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.50Å
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R-factor:
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0.213
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R-free:
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0.291
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Authors:
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W.N.Hunter,N.L.Ramsden,V.Ulaganathan
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Key ref:
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N.L.Ramsden
et al.
(2009).
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.
PubMed id:
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Date:
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22-Sep-08
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Release date:
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25-Aug-09
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PROCHECK
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Headers
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References
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P62617
(ISPF_ECOLI) -
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase from Escherichia coli (strain K12)
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Seq:
Struc:
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159 a.a.
157 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.4.6.1.12
- 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase.
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Reaction:
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4-CDP-2-C-methyl-D-erythritol 2-phosphate = 2-C-methyl-D-erythritol 2,4- cyclic diphosphate + CMP
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4-CDP-2-C-methyl-D-erythritol 2-phosphate
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=
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2-C-methyl-D-erythritol 2,4- cyclic diphosphate
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+
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CMP
Bound ligand (Het Group name = )
matches with 77.27% similarity
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Cofactor:
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Mn(2+) or Mg(2+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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J Med Chem
52:2531-2542
(2009)
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PubMed id:
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A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy.
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N.L.Ramsden,
L.Buetow,
A.Dawson,
L.A.Kemp,
V.Ulaganathan,
R.Brenk,
G.Klebe,
W.N.Hunter.
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ABSTRACT
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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.
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