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PDBsum entry 1oj4

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1oj4
Jmol
Contents
Protein chains
283 a.a. *
Ligands
CDM ×2
ANP ×2
Metals
_CL
Waters ×383
* Residue conservation analysis
PDB id:
1oj4
Name: Transferase
Title: Ternary complex of 4-diphosphocytidyl-2-c-methyl-d-erythritol kinase
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: Escherichia coli. Organism_taxid: 217992. Strain: o6. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Resolution:
2.01Å     R-factor:   0.167     R-free:   0.202
Authors: L.Miallau,M.S.Alphey,W.N.Hunter
Key ref:
L.Miallau et al. (2003). Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase. Proc Natl Acad Sci U S A, 100, 9173-9178. PubMed id: 12878729 DOI: 10.1073/pnas.1533425100
Date:
30-Jun-03     Release date:   31-Jul-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q8FI04  (ISPE_ECOL6) -  4-diphosphocytidyl-2-C-methyl-D-erythritol kinase
Seq:
Struc:
283 a.a.
283 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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
Bound ligand (Het Group name = CDM)
corresponds exactly
=
ADP
Bound ligand (Het Group name = ANP)
matches with 78.00% similarity
+ 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    
 
 
DOI no: 10.1073/pnas.1533425100 Proc Natl Acad Sci U S A 100:9173-9178 (2003)
PubMed id: 12878729  
 
 
Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase.
L.Miallau, M.S.Alphey, L.E.Kemp, G.A.Leonard, S.M.McSweeney, S.Hecht, A.Bacher, W.Eisenreich, F.Rohdich, W.N.Hunter.
 
  ABSTRACT  
 
4-Diphosphocytidyl-2C-methyl-d-erythritol kinase, an essential enzyme in the nonmevalonate pathway of isopentenyl diphosphate and dimethylallyl diphosphate biosynthesis, catalyzes the single ATP-dependent phosphorylation stage affording 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate. The 2-A resolution crystal structure of the Escherichia coli enzyme in a ternary complex with substrate and a nonhydrolyzable ATP analogue reveals the molecular determinants of specificity and catalysis. The enzyme subunit displays the alpha/beta fold characteristic of the galactose kinase/homoserine kinase/mevalonate kinase/phosphomevalonate kinase superfamily, arranged into cofactor and substrate-binding domains with the catalytic center positioned in a deep cleft between domains. Comparisons with related members of this superfamily indicate that the core regions of each domain are conserved, whereas there are significant differences in the substrate-binding pockets. The nonmevalonate pathway is essential in many microbial pathogens and distinct from the mevalonate pathway used by mammals. The high degree of sequence conservation of the enzyme across bacterial species suggests similarities in structure, specificity, and mechanism. Our model therefore provides an accurate template to facilitate the structure-based design of broad-spectrum antimicrobial agents.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. The reaction catalyzed by CDP-ME kinase.
Figure 5.
Fig. 5. The proposed mechanism for CDP-ME kinase.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20213667 V.Giménez-Oya, O.Villacañas, C.Obiol-Pardo, M.Antolin-Llovera, J.Rubio-Martinez, and S.Imperial (2011).
Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions.
  J Mol Recognit, 24, 71-80.  
  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
19509296 C.Fan, H.J.Fromm, and T.A.Bobik (2009).
Kinetic and functional analysis of L-threonine kinase, the PduX enzyme of Salmonella enterica.
  J Biol Chem, 284, 20240-20248.  
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.  
20064433 H.Eoh, P.Narayanasamy, A.C.Brown, T.Parish, P.J.Brennan, and D.C.Crick (2009).
Expression and characterization of soluble 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase from bacterial pathogens.
  Chem Biol, 16, 1230-1239.  
19485344 J.L.Andreassi, M.W.Vetting, P.W.Bilder, S.L.Roderick, and T.S.Leyh (2009).
Structure of the ternary complex of phosphomevalonate kinase: the enzyme and its family.
  Biochemistry, 48, 6461-6468.
PDB code: 3gon
19670211 R.Koike, A.Kidera, and M.Ota (2009).
Alteration of oligomeric state and domain architecture is essential for functional transformation between transferase and hydrolase with the same scaffold.
  Protein Sci, 18, 2060-2066.  
19198899 V.Giménez-Oya, O.Villacañas, X.Fernàndez-Busquets, J.Rubio-Martinez, and S.Imperial (2009).
Mimicking direct protein-protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach.
  J Mol Model, 15, 997.  
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
18033714 C.M.Crane, A.K.Hirsch, M.S.Alphey, T.Sgraja, S.Lauw, V.Illarionova, F.Rohdich, W.Eisenreich, W.N.Hunter, A.Bacher, and F.Diederich (2008).
Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis.
  ChemMedChem, 3, 91.
PDB codes: 2v2q 2v2v
18668260 S.M.Kim, Y.B.Kim, T.Kuzuyama, and S.U.Kim (2008).
Two copies of 4-(cytidine 5'-diphospho)-2-C-methyl-D: -erythritol kinase (CMK) gene in Ginkgo biloba: molecular cloning and functional characterization.
  Planta, 228, 941-950.  
18422643 T.Sgraja, M.S.Alphey, S.Ghilagaber, R.Marquez, M.N.Robertson, J.L.Hemmings, S.Lauw, F.Rohdich, A.Bacher, W.Eisenreich, V.Illarionova, and W.N.Hunter (2008).
Characterization of Aquifex aeolicus 4-diphosphocytidyl-2C-methyl-d-erythritol kinase - ligand recognition in a template for antimicrobial drug discovery.
  FEBS J, 275, 2779-2794.
PDB codes: 2v2z 2v34 2v8p
17154432 A.K.Hirsch, F.R.Fischer, and F.Diederich (2007).
Phosphate recognition in structural biology.
  Angew Chem Int Ed Engl, 46, 338-352.  
17361977 A.K.Hirsch, S.Lauw, P.Gersbach, W.B.Schweizer, F.Rohdich, W.Eisenreich, A.Bacher, and F.Diederich (2007).
Nonphosphate Inhibitors of IspE Protein, a Kinase in the Non-Mevalonate Pathway for Isoprenoid Biosynthesis and a Potential Target for Antimalarial Therapy.
  ChemMedChem, 2, 806-810.  
17397541 T.Sgraja, T.K.Smith, and W.N.Hunter (2007).
Structure, substrate recognition and reactivity of Leishmania major mevalonate kinase.
  BMC Struct Biol, 7, 20.
PDB codes: 2hfs 2hfu
16533036 C.Lherbet, F.Pojer, S.B.Richard, J.P.Noel, and C.D.Poulter (2006).
Absence of substrate channeling between active sites in the Agrobacterium tumefaciens IspDF and IspE enzymes of the methyl erythritol phosphate pathway.
  Biochemistry, 45, 3548-3553.  
16452427 R.M.Cornish, J.R.Roth, and C.D.Poulter (2006).
Lethal mutations in the isoprenoid pathway of Salmonella enterica.
  J Bacteriol, 188, 1444-1450.  
  16511101 E.Byres, D.M.Martin, and W.N.Hunter (2005).
A preliminary crystallographic analysis of the putative mevalonate diphosphate decarboxylase from Trypanosoma brucei.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 581-584.  
15757480 J.Wiesner, and F.Seeber (2005).
The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.
  Expert Opin Ther Targets, 9, 23-44.  
15608374 L.E.Kemp, M.S.Alphey, C.S.Bond, M.A.Ferguson, S.Hecht, A.Bacher, W.Eisenreich, F.Rohdich, and W.N.Hunter (2005).
The identification of isoprenoids that bind in the intersubunit cavity of Escherichia coli 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase by complementary biophysical methods.
  Acta Crystallogr D Biol Crystallogr, 61, 45-52.
PDB codes: 1h47 1h48
  16511114 T.Sgraja, L.E.Kemp, N.Ramsden, and W.N.Hunter (2005).
A double mutation of Escherichia coli2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase disrupts six hydrogen bonds with, yet fails to prevent binding of, an isoprenoid diphosphate.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 625-629.
PDB code: 1yqn
15568974 A.R.Grossman, M.Lohr, and C.S.Im (2004).
Chlamydomonas reinhardtii in the landscape of pigments.
  Annu Rev Genet, 38, 119-173.  
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.