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PDBsum entry 5u2s
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Transferase/DNA
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PDB id
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5u2s
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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 the d-Stereoselectivity of human DNA polymerase β.
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Authors
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R.Vyas,
A.J.Reed,
A.T.Raper,
W.J.Zahurancik,
P.C.Wallenmeyer,
Z.Suo.
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Ref.
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Nucleic Acids Res, 2017,
45,
6228-6237.
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PubMed id
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Abstract
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Nucleoside reverse transcriptase inhibitors (NRTIs) with L-stereochemistry have
long been an effective treatment for viral infections because of the strong
D-stereoselectivity exhibited by human DNA polymerases relative to viral reverse
transcriptases. The D-stereoselectivity of DNA polymerases has only recently
been explored structurally and all three DNA polymerases studied to date have
demonstrated unique stereochemical selection mechanisms. Here, we have solved
structures of human DNA polymerase β (hPolβ), in complex with
single-nucleotide gapped DNA and L-nucleotides and performed pre-steady-state
kinetic analysis to determine the D-stereoselectivity mechanism of hPolβ.
Beyond a similar 180° rotation of the L-nucleotide ribose ring seen in other
studies, the pre-catalytic ternary crystal structures of hPolβ, DNA and L-dCTP
or the triphosphate forms of antiviral drugs lamivudine ((-)3TC-TP) and
emtricitabine ((-)FTC-TP) provide little structural evidence to suggest that
hPolβ follows the previously characterized mechanisms of D-stereoselectivity.
Instead, hPolβ discriminates against L-stereochemistry through accumulation of
several active site rearrangements that lead to a decreased nucleotide binding
affinity and incorporation rate. The two NRTIs escape some of the active site
selection through the base and sugar modifications but are selected against
through the inability of hPolβ to complete thumb domain closure.
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