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PDBsum entry 1roz

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1roz
Jmol
Contents
Protein chain
336 a.a. *
Ligands
NAD ×2
Waters ×423
* Residue conservation analysis
PDB id:
1roz
Name: Transferase
Title: Deoxyhypusine synthase holoenzyme in its low ionic strength, crystal form
Structure: Deoxyhypusine synthase. Chain: a, b. Synonym: dhs. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dhps, ds. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PDB file)
Resolution:
2.21Å     R-factor:   0.178     R-free:   0.200
Authors: T.C.Umland,E.C.Wolff,M.-H.Park,D.R.Davies
Key ref:
T.C.Umland et al. (2004). A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme.NAD.inhibitor ternary complex. J Biol Chem, 279, 28697-28705. PubMed id: 15100216 DOI: 10.1074/jbc.M404095200
Date:
02-Dec-03     Release date:   13-Jul-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P49366  (DHYS_HUMAN) -  Deoxyhypusine synthase
Seq:
Struc:
369 a.a.
336 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.46  - Deoxyhypusine synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
EC 2.5.1.46
      Reaction: [eIF5A-precursor]-lysine + spermidine = [eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
[eIF5A-precursor]-lysine
+ spermidine
= [eIF5A-precursor]-deoxyhypusine
+ propane-1,3-diamine
      Cofactor: NAD(+)
NAD(+)
Bound ligand (Het Group name = NAD) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytosol   1 term 
  Biological process     positive regulation of cell proliferation   7 terms 
  Biochemical function     protein binding     3 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M404095200 J Biol Chem 279:28697-28705 (2004)
PubMed id: 15100216  
 
 
A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme.NAD.inhibitor ternary complex.
T.C.Umland, E.C.Wolff, M.H.Park, D.R.Davies.
 
  ABSTRACT  
 
Deoxyhypusine synthase catalyzes the first step in the two-step post-translational synthesis of hypusine, which is uniquely present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine synthase and eIF5A are conserved throughout the eukaryotic kingdom, and both are essential for cell proliferation and survival. A previous study (Liao, D. I., Wolff, E. C., Park, M. H., and Davies, D. R. (1998) Structure 6, 23-32) of human deoxyhypusine synthase revealed four active sites of the homotetrameric enzyme located within deep tunnels. These Form I crystals were obtained under conditions of acidic pH and high ionic strength and likely contain an inactive enzyme. Each active-site entrance is blocked by a ball-and-chain motif composed of a region of extended structure capped by a two-turn alpha-helix. We report here at 2.2 A a new Form II crystal of the deoxyhypusine synthase:NAD holoenzyme grown at low ionic strength and pH 8.0, near the optimal pH for enzymatic activity. The ball-and-chain motif could not be detected in the electron density, suggesting that it swings freely and thus it no longer obstructs the active-site entrance. The deoxyhypusine synthase competitive inhibitor N(1)-guanyl-1,7-diaminoheptane (GC(7))is observed bound within the putative active site of the enzyme in the new crystal form (Form II) after exposure to the inhibitor. This first structure of a deoxyhypusine synthase.NAD.inhibitor ternary complex under physiological conditions now provides a structural context to discuss the results of previous biochemical investigations of the deoxyhypusine synthase reaction mechanism. This structure also provides a basis for the development of improved inhibitors and antiproliferative agents.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Human DHS crystal structures. A, stereoview of the Form II DHS·NAD tetramer, with each monomer indicated by a different color and label, and NAD in red. The black diamonds indicate the general location of the active sites, and the blue spheres denote Ser28. B, the DHS Form I structure (this study), emphasizing the ball-and-chain motif obstructing an active-site entrance. C, the Rossmann fold of the DHS monomer is green, the mobile ball-and-chain is magenta, and the secondary structure labeling scheme is from Ref. 15.
Figure 4.
FIG. 4. Representations of the electrostatic surfaces surrounding an active-site tunnel entrance of the Form II human DHS crystal structure (A) and the homology model of HSS from a plant (S. vulgaris) (B). Positively and negatively charged regions are denoted as blue and red, respectively.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 28697-28705) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21463208 M.Woriedh, I.Hauber, A.L.Martinez-Rocha, C.Voigt, F.J.Maier, M.Schröder, C.Meier, J.Hauber, and W.Schäfer (2011).
Preventing fusarium head blight of wheat and cob rot of maize by inhibition of fungal deoxyhypusine synthase.
  Mol Plant Microbe Interact, 24, 619-627.  
19880510 B.Chawla, A.Jhingran, S.Singh, N.Tyagi, M.H.Park, N.Srinivasan, S.C.Roberts, and R.Madhubala (2010).
Identification and characterization of a novel deoxyhypusine synthase in Leishmania donovani.
  J Biol Chem, 285, 453-463.  
19956997 B.Kerscher, E.Nzukou, and A.Kaiser (2010).
Assessment of deoxyhypusine hydroxylase as a putative, novel drug target.
  Amino Acids, 38, 471-477.  
  19825182 M.Hoque, H.M.Hanauske-Abel, P.Palumbo, D.Saxena, D.D'Alliessi Gandolfi, M.H.Park, T.Pe'ery, and M.B.Mathews (2009).
Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A.
  Retrovirology, 6, 90.  
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.  
18256853 S.Specht, S.R.Sarite, I.Hauber, J.Hauber, U.F.Görbig, C.Meier, D.Bevec, A.Hoerauf, and A.Kaiser (2008).
The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase.
  Parasitol Res, 102, 1177-1184.  
17476569 E.C.Wolff, K.R.Kang, Y.S.Kim, and M.H.Park (2007).
Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification.
  Amino Acids, 33, 341-350.  
17391984 J.K.Huang, Y.Cui, C.H.Chen, D.Clampitt, C.T.Lin, and L.Wen (2007).
Molecular cloning and functional expression of bovine deoxyhypusine hydroxylase cDNA and homologs.
  Protein Expr Purif, 54, 126-133.  
16371467 J.H.Park, L.Aravind, E.C.Wolff, J.Kaevel, Y.S.Kim, and M.H.Park (2006).
Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme.
  Proc Natl Acad Sci U S A, 103, 51-56.  
17042947 J.T.Njuguna, M.Nassar, A.Hoerauf, and A.E.Kaiser (2006).
Cloning, expression and functional activity of deoxyhypusine synthase from Plasmodium vivax.
  BMC Microbiol, 6, 91.  
16452303 M.H.Park (2006).
The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A).
  J Biochem, 139, 161-169.  
16550432 M.Saeftel, R.S.Sarite, T.Njuguna, U.Holzgrabe, D.Ulmer, A.Hoerauf, and A.Kaiser (2006).
Piperidones with activity against Plasmodium falciparum.
  Parasitol Res, 99, 281-286.  
15869381 D.Davies, and D.Davies (2005).
A quiet life with proteins.
  Annu Rev Biophys Biomol Struct, 34, 1.  
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.