4PHD

Structure of human DNA polymerase beta complexed with A in the template base paired with incoming non-hydrolyzable CTP and MANGANESE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.245 

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Literature

The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase beta.

Koag, M.C.Nam, K.Lee, S.

(2015) Nucleic Acids Res 42: 11233-11245

  • DOI: https://doi.org/10.1093/nar/gku789
  • Primary Citation of Related Structures:  
    4PGQ, 4PGX, 4PHA, 4PHD

  • PubMed Abstract: 

    To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β (polβ), we report four crystal structures of polβ complexed with dG•dTTP and dA•dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg(2+)-bound ground-state structures show that the dA•dCTP-Mg2+ complex adopts an 'intermediate' protein conformation while the dG•dTTP-Mg2+ complex adopts an open protein conformation. The Mn(2+)-bound 'pre-chemistry-state' structures show that the dA•dCTP-Mn2+ complex is structurally very similar to the dA•dCTP-Mg2+ complex, whereas the dG•dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson-Crick-like dG•dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that polβ increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, polβ appears to allow only a Watson-Crick-like conformation for purine•pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson-Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of polβ.


  • Organizational Affiliation

    Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA polymerase beta329Homo 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*GP*AP*CP*AP*TP*CP*GP*CP*AP*TP*CP*AP*GP*C)-3')B [auth T]16synthetic construct
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*A)-3')C [auth P]10synthetic construct
Sequence Annotations
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  • Reference Sequence

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.21 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.245 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.245α = 90
b = 79.954β = 108.88
c = 54.403γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction

Structure Validation

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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: 2014-09-24
    Type: Initial release
  • Version 1.1: 2014-10-08
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • 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