1RQD

deoxyhypusine synthase holoenzyme in its low ionic strength, high pH crystal form with the inhibitor GC7 bound in the active site


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

A New Crystal Structure of Deoxyhypusine Synthase Reveals the Configuration of the Active Enzyme and of an Enzyme-NAD-Inhibitor Ternary Complex

Umland, T.C.Wolff, E.C.Park, M.-H.Davies, D.R.

(2004) J Biol Chem 279: 28697-28705

  • DOI: https://doi.org/10.1074/jbc.M404095200
  • Primary Citation of Related Structures:  
    1RLZ, 1ROZ, 1RQD

  • PubMed 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.


  • Organizational Affiliation

    Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxyhypusine synthase
A, B
369Homo sapiensMutation(s): 0 
Gene Names: DHPSDS
EC: 2.5.1.46
UniProt & NIH Common Fund Data Resources
Find proteins for P49366 (Homo sapiens)
Explore P49366 
Go to UniProtKB:  P49366
PHAROS:  P49366
GTEx:  ENSG00000095059 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49366
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.78α = 90
b = 104.78β = 90
c = 159.25γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-07-13
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2014-11-12
    Changes: Structure summary
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description