PDBsum entry 1uek

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protein links
Transferase PDB id
Protein chain
268 a.a. *
Waters ×198
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of 4-(cytidine 5'-diphospho)-2c-methyl-d- erythritol kinase
Structure: 4-(cytidine 5'-diphospho)-2c-methyl-d-erythritol kinase. Chain: a. Engineered: yes
Source: Thermus thermophilus. Organism_taxid: 274. Gene: ychb. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.70Å     R-factor:   0.184     R-free:   0.218
Authors: T.Wada,S.Kuramitsu,S.Yokoyama,J.R.H.Tame,S.Y.Park,Riken Structural Genomics/proteomics Initiative (Rsgi)
Key ref:
T.Wada et al. (2003). Crystal structure of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis. J Biol Chem, 278, 30022-30027. PubMed id: 12771135 DOI: 10.1074/jbc.M304339200
17-May-03     Release date:   17-Jun-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P83700  (ISPE_THET8) -  4-diphosphocytidyl-2-C-methyl-D-erythritol kinase
275 a.a.
268 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 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
+ 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
+ 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  


DOI no: 10.1074/jbc.M304339200 J Biol Chem 278:30022-30027 (2003)
PubMed id: 12771135  
Crystal structure of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis.
T.Wada, T.Kuzuyama, S.Satoh, S.Kuramitsu, S.Yokoyama, S.Unzai, J.R.Tame, S.Y.Park.
The crystal structure of the enzyme 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol (CDP-ME) kinase from the thermophilic bacterium Thermus thermophilus HB8 has been determined at 1.7-A resolution. This enzyme catalyzes phosphorylation of the 2-hydroxyl group of CDP-ME, the fourth step of the non-mevalonate pathway, which is essential for isoprenoid biosynthesis in several pathogenic microorganisms. Since this pathway is absent in humans, it is an important target for the development of novel antimicrobial compounds. The structure of the enzyme is similar to the structures of mevalonate kinase and homoserine kinase, members of the GHMP superfamily. Lys8 and Asp125 are active site residues in mevalonate kinase that also appear to play a catalytic role in CDP-ME kinase. Both the mevalonate and the non-mevalonate pathways therefore involve closely related kinases with similar mechanisms. Assaying the enzyme showed that CDP-ME kinase will phosphorylate CDP-ME but not 4-(uridine 5'-diphospho)-2-C-methyl-D-erythritol, indicating the substrate pyrimidine moiety is involved in important interactions with the enzyme.
  Selected figure(s)  
Figure 1.
FIG. 1. Non-mevalonate pathway. The pathway is composed of seven reaction steps and starts with pyruvate and glyceraldehyde-3-phosphate. The enzyme CDP-ME kinase converts CDP-ME into CDP-ME 2-phosphate at the fourth step of the pathway. DXP, 1-deoxy-D-xylulose 5-phosphate; MECDP, 2-C-methyl-D-erythritol 2,4-cyclo-diphosphate; HMBDP, 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate.
Figure 4.
FIG. 4. Putative catalytic site of CMK. a, a stereo 2F[o] - F[c] electron density map with a ball-and-stick model around Lys8, Phe^30, and Asp125, which are represented at 1.3 contour level. b, ADP (blue) and ATP (yellow) modeled in anti and syn conformations, respectively. The side chains of Lys8, Asn58, Lys83, Ser95, and Asp125 are represented as ball-and-stick models, and oxygen atoms and nitrogen atoms in these side chains are colored red and blue. The orientation is rotated about 90° around the vertical axis and turned 90° clockwise from that of Fig. 3.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 30022-30027) copyright 2003.  
  Figures were selected by an automated process.  

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.  
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.  
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
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
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.  
17400916 J.L.Andreassi, P.W.Bilder, M.W.Vetting, S.L.Roderick, and T.S.Leyh (2007).
Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonate.
  Protein Sci, 16, 983-989.
PDB code: 2oi2
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.  
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.  
15169949 D.Krepkiy, and H.M.Miziorko (2004).
Identification of active site residues in mevalonate diphosphate decarboxylase: implications for a family of phosphotransferases.
  Protein Sci, 13, 1875-1881.  
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.