1RH0

Crystal structure of human Tyrosyl-DNA Phosphodiesterase complexed with vanadate, octopamine and trinucleotide GTT


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 

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This is version 1.4 of the entry. See complete history


Literature

Explorations of peptide and oligonucleotide binding sites of tyrosyl-DNA phosphodiesterase using vanadate complexes.

Davies, D.R.Interthal, H.Champoux, J.J.Hol, W.G.

(2004) J Med Chem 47: 829-837

  • DOI: https://doi.org/10.1021/jm030487x
  • Primary Citation of Related Structures:  
    1RFF, 1RFI, 1RG1, 1RG2, 1RGT, 1RGU, 1RH0

  • PubMed Abstract: 

    Tyrosyl-DNA phosphodiesterase (Tdp1) catalyzes the hydrolysis of a phosphodiester bond between a tyrosine residue and a DNA 3' phosphate and functions as a DNA repair enzyme that cleaves stalled topoisomerase I-DNA complexes. We previously determined a procedure to crystallize a quaternary complex containing Tdp1, vanadate, a DNA oligonucleotide, and a tyrosine-containing peptide that mimics the transition state for hydrolysis of the Tdp1 substrate. Here, the ability of vanadate to accept a variety of different ligands is exploited to produce several different quaternary complexes with a variety of oligonucleotides, and peptides or a tyrosine analogue, in efforts to explore the binding properties of the Tdp1 DNA and peptide binding clefts. Eight crystal structures of Tdp1 with vanadate, oligonucleotides, and peptides or peptide analogues were determined. These structures demonstrated that Tdp1 is able to bind substituents with limited sequence variation in the polypeptide moiety and also bind oligonucleotides with sequence variation at the 3' end. Additionally, the tyrosine analogue octopamine can replace topoisomerase I derived peptides as the apical ligand to vanadate. The versatility of this system suggests that the formation of quaternary complexes around vanadate could be adapted to become a useful method for structure-based inhibitor design and has the potential to be generally applicable to other enzymes that perform chemistry on phosphate esters.


  • Organizational Affiliation

    Department of Biochemistry, P.O. Box 357742, School of Medicine, University of Washington, Seattle, Washington 98195-7242, USA.


Macromolecules

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosyl-DNA phosphodiesterase 1C [auth A],
D [auth B]
485Homo sapiensMutation(s): 3 
Gene Names: TDP1
EC: 3.1.4
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NUW8 (Homo sapiens)
Explore Q9NUW8 
Go to UniProtKB:  Q9NUW8
PHAROS:  Q9NUW8
GTEx:  ENSG00000042088 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NUW8
Sequence Annotations
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  • Reference Sequence

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Entity ID: 1
MoleculeChains LengthOrganismImage
5'-D(*GP*TP*T)-3'A [auth D],
B [auth F]
3N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.692α = 90
b = 104.75β = 90
c = 194.033γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-02
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-23
    Changes: Data collection, Refinement description