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EMBO J ; 34(14): 1959-70, 2015 Jul 14.
Article in English | MEDLINE | ID: mdl-26056153

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.


Subject(s)
DNA-Directed DNA Polymerase/chemistry , DNA-Directed DNA Polymerase/metabolism , Zalcitabine/toxicity , Amino Acid Sequence , Base Sequence , Binding Sites , Catalytic Domain , Crystallography, X-Ray , DNA Polymerase gamma , DNA, Mitochondrial/metabolism , DNA-Directed DNA Polymerase/genetics , Humans , Models, Molecular , Molecular Sequence Data , Mutation , Protein Conformation , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/toxicity , Zalcitabine/chemistry , Zalcitabine/metabolism
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