3QI5

Crystal structure of human alkyladenine DNA glycosylase in complex with 3,N4-ethenocystosine containing duplex DNA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural Basis for the Inhibition of Human Alkyladenine DNA Glycosylase (AAG) by 3,N4-Ethenocytosine-containing DNA.

Lingaraju, G.M.Davis, C.A.Setser, J.W.Samson, L.D.Drennan, C.L.

(2011) J Biol Chem 286: 13205-13213

  • DOI: https://doi.org/10.1074/jbc.M110.192435
  • Primary Citation of Related Structures:  
    3QI5

  • PubMed Abstract: 

    Reactive oxygen and nitrogen species, generated by neutrophils and macrophages in chronically inflamed tissues, readily damage DNA, producing a variety of potentially genotoxic etheno base lesions; such inflammation-related DNA damage is now known to contribute to carcinogenesis. Although the human alkyladenine DNA glycosylase (AAG) can specifically bind DNA containing either 1,N(6)-ethenoadenine (εA) lesions or 3,N(4)-ethenocytosine (εC) lesions, it can only excise εA lesions. AAG binds very tightly to DNA containing εC lesions, forming an abortive protein-DNA complex; such binding not only shields εC from repair by other enzymes but also inhibits AAG from acting on other DNA lesions. To understand the structural basis for inhibition, we have characterized the binding of AAG to DNA containing εC lesions and have solved a crystal structure of AAG bound to a DNA duplex containing the εC lesion. This study provides the first structure of a DNA glycosylase in complex with an inhibitory base lesion that is induced endogenously and that is also induced upon exposure to environmental agents such as vinyl chloride. We identify the primary cause of inhibition as a failure to activate the nucleotide base as an efficient leaving group and demonstrate that the higher binding affinity of AAG for εC versus εA is achieved through formation of an additional hydrogen bond between Asn-169 in the active site pocket and the O(2) of εC. This structure provides the basis for the design of AAG inhibitors currently being sought as an adjuvant for cancer chemotherapy.


  • Organizational Affiliation

    Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA-3-methyladenine glycosylase
A, B
219Homo sapiensMutation(s): 0 
Gene Names: MPGAAGANPGMID1
EC: 3.2.2.21
UniProt & NIH Common Fund Data Resources
Find proteins for P29372 (Homo sapiens)
Explore P29372 
Go to UniProtKB:  P29372
PHAROS:  P29372
GTEx:  ENSG00000103152 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29372
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA (5'-D(*GP*AP*CP*AP*TP*GP*(EDC)P*TP*TP*GP*CP*CP*T)-3')
C, E
13N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*GP*GP*CP*AP*AP*GP*CP*AP*TP*GP*TP*CP*A)-3')
D, F
13N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.239 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.226α = 81.23
b = 41.22β = 88.4
c = 82.144γ = 89.15
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-01-18
    Changes: Atomic model
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description