The human DNA polymerase gamma (Pol c) is responsible for DNA replication in mitochondria. Pol c is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol c-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol c active site almost identically to the substrate dCTP, providing a structural basis for Pol c-mediated drug toxicity. When compared to the apo form, Pol c 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 cB, 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 c mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol c, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol c-mediated drug toxicity.
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