1LPQ

Human DNA Topoisomerase I (70 Kda) In Non-Covalent Complex With A 22 Base Pair DNA Duplex Containing an 8-oxoG Lesion


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.14 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.256 

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This is version 1.4 of the entry. See complete history


Literature

8-Oxoguanine rearranges the active site of human topoisomerase I

Lesher, D.T.Pommier, Y.Stewart, L.Redinbo, M.R.

(2002) Proc Natl Acad Sci U S A 99: 12102-12107

  • DOI: https://doi.org/10.1073/pnas.192282699
  • Primary Citation of Related Structures:  
    1LPQ

  • PubMed Abstract: 

    7,8-Dihydro-8-oxoguanine (8-oxoG) is the most common form of oxidative DNA damage in human cells. Biochemical studies have shown that 8-oxoG decreases the DNA cleavage activity of human topoisomerase I, an enzyme vital to DNA metabolism and stability. We present the 3.1-A crystal structure of human topoisomerase I in noncovalent complex with a DNA oligonucleotide containing 8-oxoG at the +1 position in the scissile strand. We find that 8-oxoG reorganizes the active site of human topoisomerase I into an inactive conformation relative to the structures of topoisomerase I-DNA complexes elucidated previously. The catalytic Tyr-723-Phe rotates away from the DNA cleavage site and packs into the body of the molecule. A second active-site residue, Arg-590, becomes disordered and is not observed in the structure. The docked, inactive conformation of Tyr-723-Phe is reminiscent of the related tyrosine recombinase family of integrases and recombinases, suggesting a common regulatory mechanism. We propose that human topoisomerase I binds to DNA first in an inactive conformation and then rearranges its active site for catalysis. 8-OxoG appears to impact topoisomerase I by stabilizing the inactive, DNA-bound state.


  • Organizational Affiliation

    Departments of Chemistry and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.


Macromolecules

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
DNA topoisomerase IC [auth A]564Homo sapiensMutation(s): 1 
EC: 5.99.1.2
UniProt & NIH Common Fund Data Resources
Find proteins for P11387 (Homo sapiens)
Explore P11387 
Go to UniProtKB:  P11387
PHAROS:  P11387
GTEx:  ENSG00000198900 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11387
Sequence Annotations
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  • Reference Sequence

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Entity ID: 1
MoleculeChains LengthOrganismImage
5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*TP*(8OG)P*GP*AP*AP*AP*AP*AP*TP*TP*TP*TP*T)-3'A [auth B]22N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
5'-D(*AP*AP*AP*AP*AP*TP*TP*TP*TP*TP*CP*CP*AP*AP*GP*TP*CP*TP*TP*TP*TP*T)-3'B [auth C]22N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.14 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.256 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.2α = 90
b = 122.5β = 97.4
c = 72γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2002-08-16
    Type: Initial release
  • Version 1.1: 2008-04-28
    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: 2024-02-14
    Changes: Data collection