2IA6

Bypass of Major Benzopyrene-dG Adduct by Y-Family DNA Polymerase with Unique Structural Gap


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.216 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment.

Bauer, J.Xing, G.Yagi, H.Sayer, J.M.Jerina, D.M.Ling, H.

(2007) Proc Natl Acad Sci U S A 104: 14905-14910

  • DOI: https://doi.org/10.1073/pnas.0700717104
  • Primary Citation of Related Structures:  
    2IA6, 2IBK

  • PubMed Abstract: 

    Erroneous replication of lesions in DNA by DNA polymerases leads to elevated mutagenesis. To understand the molecular basis of DNA damage-induced mutagenesis, we have determined the x-ray structures of the Y-family polymerase, Dpo4, in complex with a DNA substrate containing a bulky DNA lesion and incoming nucleotides. The DNA lesion is derived from an environmentally widespread carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BP). The potent carcinogen BP is metabolized to diol epoxides that form covalent adducts with cellular DNA. In the present study, the major BP diol epoxide adduct in DNA, BP-N(2)-deoxyguanosine (BP-dG), was placed at a template-primer junction. Three ternary complexes reveal replication blockage, extension past a mismatched lesion, and a -1 frameshift mutation. In the productive structures, the bulky adduct is flipped/looped out of the DNA helix into a structural gap between the little finger and core domains. Sequestering of the hydrophobic BP adduct in this new substrate-binding site permits the DNA to exhibit normal geometry for primer extension. Extrusion of the lesion by template misalignment allows the base 5' to the adduct to serve as the template, resulting in a -1 frameshift. Subsequent strand realignment produces a mismatched base opposite the lesion. These structural observations, in combination with replication and mutagenesis data, suggest a model in which the additional substrate-binding site stabilizes the extrahelical nucleotide for lesion bypass and generation of base substitutions and -1 frameshift mutations.


  • Organizational Affiliation

    Department of Biochemistry, University of Western Ontario, London, ON, Canada N6A 5C1.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA polymerase IV
A, B
352Saccharolobus solfataricus P2Mutation(s): 0 
Gene Names: dbhdpo4
EC: 2.7.7.7
UniProt
Find proteins for Q97W02 (Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2))
Explore Q97W02 
Go to UniProtKB:  Q97W02
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ97W02
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
5'-D(*GP*GP*GP*GP*GP*AP*AP*GP*GP*AP*TP*TP*A)-3'
C, E
13N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
5'-D(*TP*CP*AP*TP*GP*AP*AP*TP*CP*CP*TP*TP*CP*CP*CP*CP*C)-3'
D, F
17N/A
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ATP
Query on ATP

Download Ideal Coordinates CCD File 
K [auth A],
O [auth B]
ADENOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O13 P3
ZKHQWZAMYRWXGA-KQYNXXCUSA-N
BAP
Query on BAP

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T [auth D],
V [auth F]
1,2,3-TRIHYDROXY-1,2,3,4-TETRAHYDROBENZO[A]PYRENE
C20 H16 O3
GFANZDFKCCJYRF-NSISKUIASA-N
PO4
Query on PO4

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G [auth A],
H [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

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P [auth B],
U [auth E],
X [auth F]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

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Q [auth C],
R [auth C],
S [auth C],
W [auth F]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
L [auth B],
M [auth B],
N [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.216 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.217α = 90
b = 102.58β = 90
c = 106.147γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data 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: 2007-09-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description