4TUQ: Human Dna Polymerase Beta Inserting Dcmpnpp Opposite Gg Template (gg0b)

Citation:
Abstract
Human DNA polymerase beta (polbeta) has been suggested to play a role in cisplatin resistance, especially in polbeta-overexpressing cancer cells. Polbeta 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 polbeta is unknown. To gain structural insights into the mechanism, we determined two ternary structures of polbeta 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 polbeta 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 polbeta. The Mn(2+)-bound structure shows that polbeta 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 polbeta. Overall, our studies provide the first structural insights into the mechanism of the potential polbeta-mediated cisplatin resistance.
PDB ID: 4TUQDownload
MMDB ID: 123970
PDB Deposition Date: 2014/6/24
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.37  Å
Source Organism:
Similar Structures:
Biological Unit for 4TUQ: tetrameric; determined by author and by software (PISA)
Molecular Components in 4TUQ
Label Count Molecule
Protein (1 molecule)
1
DNA Polymerase Beta(Gene symbol: POLB)
Molecule annotation
Nucleotides(3 molecules)
1
DNA (5'-d(*cp*cp*cp*ap*cp*gp*gp*cp*cp*cp*ap*tp*cp*ap*cp*c)- 3')
Molecule annotation
1
DNA (5'-d(*gp*gp*tp*gp*ap*tp*gp*gp*gp*c)-3')
Molecule annotation
1
DNA (5'-d(p*gp*tp*gp*gp*g)-3')
Molecule annotation
Chemicals (5 molecules)
1
2
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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