4TUQ

Human DNA polymerase beta inserting dCMPNPP opposite GG template (GG0b).


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Structural Basis for the Inefficient Nucleotide Incorporation Opposite Cisplatin-DNA Lesion by Human DNA Polymerase beta.

Koag, M.C.Lai, L.Lee, S.

(2014) J Biol Chem 289: 31341-31348

  • DOI: https://doi.org/10.1074/jbc.M114.605451
  • Primary Citation of Related Structures:  
    4TUP, 4TUQ, 4TUR, 4TUS

  • PubMed Abstract: 

    Human DNA polymerase β (polβ) has been suggested to play a role in cisplatin resistance, especially in polβ-overexpressing cancer cells. Polβ has been shown to accurately albeit slowly bypass the cisplatin-1,2-d(GpG) (Pt-GG) intramolecular cross-link in vitro. Currently, the structural basis for the inefficient Pt-GG bypass mechanism of polβ is unknown. To gain structural insights into the mechanism, we determined two ternary structures of polβ incorporating dCTP opposite the templating Pt-GG lesion in the presence of the active site Mg(2+) or Mn(2+). The Mg(2+)-bound structure shows that the bulky Pt-GG adduct is accommodated in the polβ active site without any steric hindrance. In addition, both guanines of the Pt-GG lesion form Watson-Crick base pairing with the primer terminus dC and the incoming dCTP, providing the structural basis for the accurate bypass of the Pt-GG adduct by polβ. The Mn(2+)-bound structure shows that polβ adopts a catalytically suboptimal semiclosed conformation during the insertion of dCTP opposite the templating Pt-GG, explaining the inefficient replication across the Pt-GG lesion by polβ. Overall, our studies provide the first structural insights into the mechanism of the potential polβ-mediated cisplatin resistance.


  • Organizational Affiliation

    From the Division of Medicinal Chemistry, College of Pharmacy, The University of Texas, Austin, Texas 78712.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA polymerase beta326Homo sapiensMutation(s): 0 
Gene Names: POLB
EC: 2.7.7.7 (PDB Primary Data), 4.2.99 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P06746 (Homo sapiens)
Explore P06746 
Go to UniProtKB:  P06746
PHAROS:  P06746
GTEx:  ENSG00000070501 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06746
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA (5'-D(*CP*CP*CP*AP*CP*GP*GP*CP*CP*CP*AP*TP*CP*AP*CP*C)-3')B [auth T]16Homo sapiens
Sequence Annotations
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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*GP*GP*TP*GP*AP*TP*GP*GP*GP*C)-3')C [auth P]10Homo sapiens
Sequence Annotations
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  • Reference Sequence

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Entity ID: 4
MoleculeChains LengthOrganismImage
DNA (5'-D(P*GP*TP*GP*GP*G)-3')5Homo sapiens
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.82α = 90
b = 80.542β = 107.69
c = 55.535γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)United StatesES23101

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-01
    Type: Initial release
  • Version 1.1: 2014-10-15
    Changes: Database references
  • Version 1.2: 2014-11-19
    Changes: Database references
  • Version 1.3: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations, Other, Source and taxonomy
  • Version 1.4: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.5: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.6: 2024-03-13
    Changes: Source and taxonomy