1U45

8oxoguanine at the pre-insertion site of the polymerase active site


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

Error-prone replication of oxidatively damaged DNA by a high-fidelity DNA polymerase.

Hsu, G.W.Ober, M.Carell, T.Beese, L.S.

(2004) Nature 431: 217-221

  • DOI: https://doi.org/10.1038/nature02908
  • Primary Citation of Related Structures:  
    1U45, 1U47, 1U48, 1U49, 1U4B

  • PubMed Abstract: 

    Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.


  • Organizational Affiliation

    Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.


Macromolecules

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
DNA polymerase IC [auth A]580Geobacillus stearothermophilusMutation(s): 0 
EC: 2.7.7.7
UniProt
Find proteins for P52026 (Geobacillus stearothermophilus)
Explore P52026 
Go to UniProtKB:  P52026
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52026
Sequence Annotations
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  • Reference Sequence

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Entity ID: 1
MoleculeChains LengthOrganismImage
DNA primer strandA [auth B]10N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA template strand with 8-oxoguanineB [auth C]15N/A
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose
D
2N/A
Glycosylation Resources
GlyTouCan:  G05551OP
GlyCosmos:  G05551OP
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.281α = 90
b = 93.141β = 90
c = 106.02γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-09-14
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-08-23
    Changes: Data collection, Database references, Refinement description, Structure summary