5III

Crystal structure of the pre-catalytic ternary complex of DNA polymerase lambda with a templating 8-oxo-dG and an incoming dATP

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 

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This is version 1.3 of the entry. See complete history. 


Literature

A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG.

Burak, M.J., Guja, K.E., Hambardjieva, E., Derkunt, B., Garcia-Diaz, M.

(2016) EMBO J 35: 2045-2059

  • DOI: https://doi.org/10.15252/embj.201694332
  • Primary Citation of Related Structures:  
    5III, 5IIJ, 5IIK, 5IIL, 5IIM, 5IIN, 5IIO

  • PubMed Abstract: 

    8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dG:dA mispairs are removed through DNA polymerase lambda (Pol λ)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol λ. We demonstrate that Pol λ has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn-conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER.

    • Organizational Affiliation: 

    Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA polymerase lambda334Homo sapiensMutation(s): 0 
Gene Names: POLL
EC: 2.7.7.7 (PDB Primary Data), 4.2.99 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UGP5 (Homo sapiens)
Explore Q9UGP5 
Go to UniProtKB:  Q9UGP5
PHAROS:  Q9UGP5
GTEx:  ENSG00000166169 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UGP5
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA (5'-D(P*GP*CP*CP*G)-3')B [auth D]4synthetic construct
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*CP*AP*GP*TP*AP*(DOC))-3')C [auth P]6synthetic construct
Sequence Annotations
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  • Reference Sequence

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Entity ID: 4
MoleculeChains LengthOrganismImage
DNA (5'-D(*CP*GP*GP*CP*(8OG)P*GP*TP*AP*CP*TP*G)-3')D [auth T]11synthetic construct
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.848α = 90
b = 62.681β = 90
c = 140.024γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
autoPROCdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-17
    Type: Initial release
  • Version 1.1: 2016-09-28
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description