4QWC

Ternary Crystal Structures of a Y-family DNA polymerase DPO4 from Sulfobus Solfataricus in Comples with DNA and L-DCDP

Summary for 4QWC

• Entry DOI: 10.2210/pdb4qwc/pdb
• Related: 4QW8 4QW9 4QWA 4QWB 4QWD 4QWE
• Descriptor: DNA polymerase IV, DNA (5'-D(*GP*GP*CP*TP*AP*CP*AP*GP*GP*AP*CP*TP*C)-3'), DNA (5'-D(*TP*TP*CP*AP*GP*GP*AP*GP*TP*CP*CP*TP*GP*TP*AP*GP*CP*C)-3'), ... (7 entities in total)
• Functional Keywords: y-family dna polymerase, transferase-dna complex, polymerase, transferase/dna
• Biological source: Saccharolobus solfataricus P2; More
• Cellular location: Cytoplasm (Probable): Q97W02
• Total number of polymer chains: 6
• Total formula weight: 98527.64

Authors

Vyas, R.,Suo, Z. (deposition date: 2014-07-16, release date: 2014-08-27, Last modification date: 2023-09-20)

Primary citation

Gaur, V.,Vyas, R.,Fowler, J.D.,Efthimiopoulos, G.,Feng, J.Y.,Suo, Z.
Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase.
Nucleic Acids Res., 42:9984-9995, 2014

PubMed 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° 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.

PubMed: 25104018
DOI: 10.1093/nar/gku709

Experimental method

X-RAY DIFFRACTION (2.4 Å)