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Title
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Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance.
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Authors
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C.Tantillo,
J.Ding,
A.Jacobo-Molina,
R.G.Nanni,
P.L.Boyer,
S.H.Hughes,
R.Pauwels,
K.Andries,
P.A.Janssen,
E.Arnold.
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Ref.
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J Mol Biol, 1994,
243,
369-387.
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PubMed id
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Abstract
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The locations of HIV-1 RT nucleoside and non-nucleoside inhibitor-binding sites
and inhibitor-resistance mutations are analyzed in the context of the
three-dimensional structure of the enzyme and implications for mechanisms of
drug inhibition and resistance are discussed. In order to help identify residues
that may play a role in inhibitor binding, solvent accessibilities of amino
acids that comprise the inhibitor-binding sites in the structure of HIV-1 RT
complexed with a dsDNA template-primer are analyzed. While some mutations that
cause resistance to nucleoside analogs, such as AZT, ddI, and ddC, are located
near enough to the dNTP-binding site to directly interfere with binding of
nucleoside analogs, many are located away from the dNTP-binding site and more
likely confer resistance by other mechanisms. Many of the latter mutations are
located on the surface of the DNA-binding cleft and may lead to altered
template-primer positioning or conformation, causing a distortion of the
geometry of the polymerase active site and consequent discrimination between
normal and altered dNTP substrates. Other nucleoside analog-resistance mutations
located on the periphery of the dNTP-binding site may exert their effects via
altered interactions with dNTP-binding site residues. The structure of the
hydrophobic region in HIV-1 RT that binds non-nucleoside inhibitors, for
example, nevirapine and TIBO, has been analyzed in the absence of bound ligand.
The pocket that is present when non-nucleoside inhibitors are bound is not
observed in the inhibitor-free structure of HIV-1 RT with dsDNA. In particular
it is filled by Tyr181 and Tyr188, suggesting that the pocket is formed
primarily by rotation of these large aromatic side-chains. Existing biochemical
data, taken together with the three-dimensional structure of HIV-1 RT, makes it
possible to propose potential mechanisms of inhibition by non-nucleoside
inhibitors. One such mechanism is local distortion of HIV-1 RT structural
elements thought to participate in catalysis: the beta 9-beta 10 hairpin (which
contains polymerase active site residues) and the beta 12-beta 13 hairpin
("primer grip"). An alternative possibility is restricted mobility of the p66
thumb subdomain, which is supported by the observation that structural elements
of the non-nucleoside inhibitor-binding pocket may act as a "hinge" for the
thumb.(ABSTRACT TRUNCATED AT 400 WORDS)
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