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Title
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Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.
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Authors
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D.M.Himmel,
K.A.Maegley,
T.A.Pauly,
J.D.Bauman,
K.Das,
C.Dharia,
A.D.Clark,
K.Ryan,
M.J.Hickey,
R.A.Love,
S.H.Hughes,
S.Bergqvist,
E.Arnold.
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Ref.
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Structure, 2009,
17,
1625-1635.
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PubMed id
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Abstract
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Novel inhibitors are needed to counteract the rapid emergence of drug-resistant
HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase
H (RNH) enzymatic activities, but approved drugs that inhibit RT target the
polymerase. Inhibitors that act against new targets, such as RNH, should be
effective against all of the current drug-resistant variants. Here, we present
2.80 A and 2.04 A resolution crystal structures of an RNH inhibitor,
beta-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an
isolated RNH domain. beta-thujaplicinol chelates two divalent metal ions at the
RNH active site. We provide biochemical evidence that beta-thujaplicinol is a
slow-binding RNH inhibitor with noncompetitive kinetics and suggest that it
forms a tropylium ion that interacts favorably with RT and the RNA:DNA substrate.
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