Abstract
Human DNA polymerase gamma (Pol γ) is the sole enzyme with DNA synthesis activity in mitochondria. Pol γ is particularly susceptible to inhibition by dideoxynucleoside‐based inhibitors designed to fight viral infection. We report crystal structures of replicating Pol γ ‐DNA complex bound to either a substrate or Zalcitabine, a inhibitor designed for HIV reverse transcriptase. The structures reveal that Zalcitabine binds to Pol g active site almost identically to the normal substrate dCTP, providing a structural basis for Pol γ ‐mediated drug toxicity. Compared to apo Pol γ, the ternary complex undergoes intra‐ and inter‐subunit conformational changes upon binding to primer/template DNA. The accessory subunit Pol γB has no intrinsic enzymatic activity and does not contact the primer/template DNA directly; it serves as an allosteric regulator for holoenzyme activities. These structures suggest a mechanism for the processivity of the holoenzyme, and provide a model for understanding the deleterious effects of Pol γ mutations implicated in human diseases.
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