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PDBsum entry 4ztz
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DNA binding protein/DNA
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PDB id
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4ztz
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References listed in PDB file
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Key reference
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Title
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Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase.
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Authors
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M.R.Szymanski,
V.B.Kuznetsov,
C.Shumate,
Q.Meng,
Y.S.Lee,
G.Patel,
S.Patel,
Y.W.Yin.
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Ref.
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Embo J, 2015,
34,
1959-1970.
[DOI no: ]
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PubMed id
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Abstract
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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.
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