4QWB: Crystal Structure Of Dpo4 Linker Region P236a Mutant With An Incoming D-dcdp

Citation:
Abstract
Considering that all natural nucleotides (D-dNTPs) and the building blocks (D-dNMPs) of DNA chains possess D-stereochemistry, DNA polymerases and reverse transcriptases (RTs) likely possess strongD-stereoselectivity by preferably binding and incorporating D-dNTPs over unnatural L-dNTPs during DNA synthesis. Surprisingly, a structural basis for the discrimination against L-dNTPs by DNA polymerases or RTs has not been established although L-deoxycytidine analogs (lamivudine and emtricitabine) and L-thymidine (telbivudine) have been widely used as antiviral drugs for years. Here we report seven high-resolution ternary crystal structures of a prototype Y-family DNA polymerase, DNA, and D-dCTP, D-dCDP, L-dCDP, or the diphosphates and triphosphates of lamivudine and emtricitabine. These structures reveal that relative to D-dCTP, each of these L-nucleotides has its sugar ring rotated by 180 degrees with an unusual O4'-endo sugar puckering and exhibits multiple triphosphate-binding conformations within the active site of the polymerase. Such rare binding modes significantly decrease the incorporation rates and efficiencies of these L-nucleotides catalyzed by the polymerase.
PDB ID: 4QWBDownload
MMDB ID: 122757
PDB Deposition Date: 2014/7/16
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Sulfolobus solfataricus P2
Similar Structures:
Biological Unit for 4QWB: trimeric; determined by author and by software (PISA)
Molecular Components in 4QWB
Label Count Molecule
Protein (1 molecule)
1
DNA Polymerase IV(Gene symbol: SSO_RS11880)
Molecule annotation
Nucleotides(2 molecules)
1
DNA (5'-d(*gp*gp*cp*tp*ap*cp*ap*gp*gp*ap*cp*tp*(doc))-3')
Molecule annotation
1
DNA (5'- D(*tp*tp*cp*ap*gp*gp*ap*gp*tp*cp*cp*tp*gp*tp*ap*gp*cp*c)-3')
Molecule annotation
Chemicals (12 molecules)
1
1
2
4
3
4
4
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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