1Z36

Crystal structure of Trichomonas vaginalis purine nucleoside phosphorylase complexed with formycin A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 

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This is version 1.3 of the entry. See complete history


Literature

Identification of a subversive substrate of Trichomonas vaginalis purine nucleoside phosphorylase and the crystal structure of the enzyme-substrate complex.

Zang, Y.Wang, W.H.Wu, S.W.Ealick, S.E.Wang, C.C.

(2005) J Biol Chem 280: 22318-22325

  • DOI: https://doi.org/10.1074/jbc.M501843200
  • Primary Citation of Related Structures:  
    1Z33, 1Z34, 1Z35, 1Z36, 1Z37, 1Z38, 1Z39

  • PubMed Abstract: 

    Trichomonas vaginalis is an anaerobic protozoan parasite that causes trichomoniasis, a common sexually transmitted disease with worldwide impact. One of the pivotal enzymes in its purine salvage pathway, purine nucleoside phosphorylase (PNP), shows physical properties and substrate specificities similar to those of the high molecular mass bacterial PNPs but differing from those of human PNP. While carrying out studies to identify inhibitors of T. vaginalis PNP (TvPNP), we discovered that the nontoxic nucleoside analogue 2-fluoro-2'-deoxyadenosine (F-dAdo) is a "subversive substrate." Phosphorolysis by TvPNP of F-dAdo, which is not a substrate for human PNP, releases highly cytotoxic 2-fluoroadenine (F-Ade). In vitro studies showed that both F-dAdo and F-Ade exert strong inhibition of T. vaginalis growth with estimated IC(50) values of 106 and 84 nm, respectively, suggesting that F-dAdo might be useful as a potential chemotherapeutic agent against T. vaginalis. To understand the basis of TvPNP specificity, the structures of TvPNP complexed with F-dAdo, 2-fluoroadenosine, formycin A, adenosine, inosine, or 2'-deoxyinosine were determined by x-ray crystallography with resolutions ranging from 2.4 to 2.9 A. These studies showed that the quaternary structure, monomer fold, and active site are similar to those of Escherichia coli PNP. The principal active site difference is at Thr-156, which is alanine in E. coli PNP. In the complex of TvPNP with F-dAdo, Thr-156 causes the purine base to tilt and shift by 0.5 A as compared with the binding scheme of F-dAdo in E. coli PNP. The structures of the TvPNP complexes suggest opportunities for further improved subversive substrates beyond F-dAdo.


  • Organizational Affiliation

    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
purine nucleoside phosphorylase235Trichomonas vaginalisMutation(s): 0 
EC: 2.4.2.1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMC
Query on FMC

Download Ideal Coordinates CCD File 
B [auth A](1S)-1-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1,4-anhydro-D-ribitol
C10 H13 N5 O4
KBHMEHLJSZMEMI-KSYZLYKTSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 
  • Space Group: P 41 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.8α = 90
b = 136.8β = 90
c = 136.8γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
SCALEPACKdata scaling
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: 2005-03-29
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description