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Transferase PDB id
Protein chain
225 a.a. *
Waters ×103
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of 4-diphosphocytidyl-2-c-methylerythritol synthetase (ygbp) involved in mevalonate independent isopre biosynthesis, complexed with cdp-me and mg2+
Structure: 4-diphosphocytidyl-2-c-methylerythritol synthetas chain: a. Engineered: yes
Source: Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: ispd. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
1.82Å     R-factor:   0.222     R-free:   0.273
Authors: S.B.Richard,M.E.Bowman,W.Kwiatkowski,I.Kang,C.Chow,A.Lillo,D J.P.Noel
Key ref:
S.B.Richard et al. (2001). Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate- independent isoprenoid biosynthesis. Nat Struct Biol, 8, 641-648. PubMed id: 11427897 DOI: 10.1038/89691
14-May-01     Release date:   14-Nov-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q46893  (ISPD_ECOLI) -  2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase
236 a.a.
225 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: CTP + 2-C-methyl-D-erythritol 4-phosphate = diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
+ 2-C-methyl-D-erythritol 4-phosphate
= diphosphate
4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
Bound ligand (Het Group name = CDM)
corresponds exactly
      Cofactor: Manganese or magnesium
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     catalytic activity     6 terms  


DOI no: 10.1038/89691 Nat Struct Biol 8:641-648 (2001)
PubMed id: 11427897  
Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate- independent isoprenoid biosynthesis.
S.B.Richard, M.E.Bowman, W.Kwiatkowski, I.Kang, C.Chow, A.M.Lillo, D.E.Cane, J.P.Noel.
The YgbP protein of Escherichia coli encodes the enzyme 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) synthetase, a member of the cytidyltransferase family of enzymes. CDP-ME is an intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, algae, the plant plastids and the malaria parasite. Because vertebrates synthesize isoprenoid precursors using a mevalonate pathway, CDP-ME synthetase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal and antimalarial drugs. The high-resolution structures of E. coli CDP-ME synthetase in the apo form and complexed with both CTP-Mg2+ and CDP-ME-Mg2+ reveal the stereochemical principles underlying both substrate and product recognition as well as catalysis in CDP-ME synthetase. Moreover, these complexes represent the first experimental structures for any cytidyltransferase with both substrates and products bound.
  Selected figure(s)  
Figure 1.
Figure 1. Biosynthesis of the isoprenoid precursor isopentenyl diphosphate (IPP, 8) via the alternative, mevalonate-independent DXP/MEP pathway. All reactions are depicted in the forward direction. The synthesis of the C5 IPP skeleton begins with the condensation of a C2 moiety from the decarboxylation of pyruvate (1) and a C3 moiety from glyceraldehyde 3-phosphate (2) to form 1-deoxy-D-xylulose 5-phosphate (DXP, 3) through the action of DXP synthase^32, 33 (DXPS or DXS). Next, DXP is converted into 2-C-methyl-D-erythritol 4-phosphate (MEP, 4) by DXP reductoisomerase^34, 35 (DXPR or DXR) and subsequently transformed into 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME, 5) by CDP-ME synthetase^6, 7 (YgbP protein). Fosmidomycin acts as an effective inhibitor of DXPR3. CDP-ME is phosphorylated on the 2-hydroxy group to form 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-MEP; 6) in an ATP-dependent reaction by the enzyme CDP-ME kinase encoded by the ychB gene of E. coli36, 37. Subsequent formation of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (7) is catalyzed by the enzyme MECDP synthase encoded by the gene ygbB^17, 38. Additional steps, which remain to be elucidated, ultimately form IPP (8).
Figure 3.
Figure 3. Schematic and structural view of the CDP-ME synthetase active site. a, Schematic representation of the CDP-ME synthase active site. The panel depicts the cytidine binding site common to both the CTP and CDP-ME complexes. In addition, this panel illustrates schematically the hydrogen and coordination bonds to CTP and Mg2+, respectively. b, The putative role of side chains in the catalytic mechanism of CDP-ME synthetase. Green dotted lines denote hydrogen bonds. The black arrows represent hypothetical electron flow during both the nucleophilic attack on the CTP -phosphate and the breakdown of the putative pentacoordinate transition state. c, Schematic representation of the CDP-ME -Mg2+ binding site. Recognition of the CDP-ME product is accomplished using an extensive set of hydrogen-bonding interactions that includes residues from both polypeptide chains of the CDP-ME synthetase homodimer. d, Stereo view of the SIGMAA^20 weighted |2F[o] - F[c]| electron density map contoured at 1.0 around the CTP -Mg2+ complex at 1.5 resolution. e, Stereo view of the SIGMAA^20 weighted |2F[o] - F[c]| electron density map contoured at 1.0 around the CDP-ME -Mg2+ complex at 1.8 resolution. The depicted Mg2+ ion may possibly be a water molecule; however, the position of the modeled Mg2+ ion / water molecule overlaps with the Mg2+ site in the CTP -Mg2+ complex.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 641-648) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22522420 T.Willer, H.Lee, M.Lommel, T.Yoshida-Moriguchi, Bernabe, D.Venzke, S.Cirak, H.Schachter, J.Vajsar, T.Voit, F.Muntoni, A.S.Loder, W.B.Dobyns, T.L.Winder, S.Strahl, K.D.Mathews, S.F.Nelson, S.A.Moore, and K.P.Campbell (2012).
ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome.
  Nat Genet, 44, 575-580.  
21543842 C.Björkelid, T.Bergfors, L.M.Henriksson, A.L.Stern, T.Unge, S.L.Mowbray, and T.A.Jones (2011).
Structural and functional studies of mycobacterial IspD enzymes.
  Acta Crystallogr D Biol Crystallogr, 67, 403-414.
PDB codes: 2xwl 2xwm 2xwn
19916033 C.Obiol-Pardo, A.Cordero, J.Rubio-Martinez, and S.Imperial (2010).
Homology modeling of Mycobacterium tuberculosis 2C-methyl-D-erythritol-4-phosphate cytidylyltransferase, the third enzyme in the MEP pathway for isoprenoid biosynthesis.
  J Mol Model, 16, 1061-1073.  
19668858 A.Majumdar, M.H.Shah, J.K.Bitok, M.E.Hassis-LeBeau, and C.L.Freel Meyers (2009).
Probing phosphorylation by non-mammalian isoprenoid biosynthetic enzymes using (1)H-(31)P-(31)P correlation NMR spectroscopy.
  Mol Biosyst, 5, 935-944.  
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.  
19074383 S.Baur, J.Marles-Wright, S.Buckenmaier, R.J.Lewis, and W.Vollmer (2009).
Synthesis of CDP-activated ribitol for teichoic acid precursors in Streptococcus pneumoniae.
  J Bacteriol, 191, 1200-1210.
PDB codes: 2vsh 2vsi
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
17921290 H.Eoh, A.C.Brown, L.Buetow, W.N.Hunter, T.Parish, D.Kaur, P.J.Brennan, and D.C.Crick (2007).
Characterization of the Mycobacterium tuberculosis 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase: potential for drug development.
  J Bacteriol, 189, 8922-8927.  
17442674 W.N.Hunter (2007).
The non-mevalonate pathway of isoprenoid precursor biosynthesis.
  J Biol Chem, 282, 21573-21577.  
16478479 M.Gabrielsen, J.Kaiser, F.Rohdich, W.Eisenreich, R.Laupitz, A.Bacher, C.S.Bond, and W.N.Hunter (2006).
The crystal structure of a plant 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase exhibits a distinct quaternary structure compared to bacterial homologues and a possible role in feedback regulation for cytidine monophosphate.
  FEBS J, 273, 1065-1073.
PDB code: 1w77
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
15632142 M.A.Ballicora, J.R.Dubay, C.H.Devillers, and J.Preiss (2005).
Resurrecting the ancestral enzymatic role of a modulatory subunit.
  J Biol Chem, 280, 10189-10195.  
15466439 M.Gabrielsen, C.S.Bond, I.Hallyburton, S.Hecht, A.Bacher, W.Eisenreich, F.Rohdich, and W.N.Hunter (2004).
Hexameric assembly of the bifunctional methylerythritol 2,4-cyclodiphosphate synthase and protein-protein associations in the deoxy-xylulose-dependent pathway of isoprenoid precursor biosynthesis.
  J Biol Chem, 279, 52753-52761.
PDB codes: 1w55 1w57
15292268 N.M.Koropatkin, and H.M.Holden (2004).
Molecular structure of alpha-D-glucose-1-phosphate cytidylyltransferase from Salmonella typhi.
  J Biol Chem, 279, 44023-44029.
PDB code: 1tzf
12831902 A.Steinbüchel (2003).
Production of rubber-like polymers by microorganisms.
  Curr Opin Microbiol, 6, 261-270.  
12878729 L.Miallau, M.S.Alphey, L.E.Kemp, G.A.Leonard, S.M.McSweeney, S.Hecht, A.Bacher, W.Eisenreich, F.Rohdich, and W.N.Hunter (2003).
Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase.
  Proc Natl Acad Sci U S A, 100, 9173-9178.
PDB code: 1oj4
11706035 B.Y.Kwak, Y.M.Zhang, M.Yun, R.J.Heath, C.O.Rock, S.Jackowski, and H.W.Park (2002).
Structure and mechanism of CTP:phosphocholine cytidylyltransferase (LicC) from Streptococcus pneumoniae.
  J Biol Chem, 277, 4343-4350.
PDB codes: 1jyk 1jyl
11741911 K.Reuter, S.Sanderbrand, H.Jomaa, J.Wiesner, I.Steinbrecher, E.Beck, M.Hintz, G.Klebe, and M.T.Stubbs (2002).
Crystal structure of 1-deoxy-D-xylulose-5-phosphate reductoisomerase, a crucial enzyme in the non-mevalonate pathway of isoprenoid biosynthesis.
  J Biol Chem, 277, 5378-5384.
PDB code: 1k5h
11997478 L.E.Kemp, C.S.Bond, and W.N.Hunter (2002).
Structure of 2C-methyl-D-erythritol 2,4- cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development.
  Proc Natl Acad Sci U S A, 99, 6591-6596.
PDB code: 1gx1
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 codes are shown on the right.