4ZTU

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

Summary for 4ZTU

• Entry DOI: 10.2210/pdb4ztu/pdb
• Related: 4ZTZ
• Descriptor: DNA polymerase subunit gamma-1, DNA polymerase subunit gamma-2, mitochondrial, DNA (25-MER), ... (6 entities in total)
• Functional Keywords: mitochondria, dna polymerase holoenzyme, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 261504.90

Authors

Szymanski, M.R.,Kuznestov, V.B.,Shumate, C.K.,Meng, Q.,Lee, Y.-S.,Patel, G.,Patel, S.S.,Yin, Y.W. (deposition date: 2015-05-15, release date: 2015-09-23, Last modification date: 2024-03-06)

Primary citation

Szymanski, M.R.,Kuznestov, V.B.,Shumate, C.K.,Meng, Q.,Lee, Y.-S.,Patel, G.,Patel, S.S.,Yin, Y.W.
Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase
EMBO J., 34:1959-, 2015

PubMed Abstract: The human DNA polymerase gamma (Pol γ) is responsible for DNA replication in mitochondria. Pol γ is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol γ-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol γ active site almost identically to the substrate dCTP, providing a structural basis for Pol γ-mediated drug toxicity. When compared to the apo form, Pol γ undergoes intra- and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol γB, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol γ mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol γ, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol γ-mediated drug toxicity.

PubMed: 26056153
DOI: 10.15252/embj.201591520

Experimental method

X-RAY DIFFRACTION (3.299 Å)