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Title
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Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors.
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Authors
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R.Esnouf,
J.Ren,
C.Ross,
Y.Jones,
D.Stammers,
D.Stuart.
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Ref.
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Nat Struct Biol, 1995,
2,
303-308.
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PubMed id
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Abstract
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The structure of unliganded HIV-1 reverse transcriptase has been determined at
2.35 A resolution and refined to an R-factor of 0.219 (for all data) with good
stereochemistry. The unliganded structure was produced by soaking out a weak
binding non-nucleoside inhibitor, HEPT, from pregrown crystals. Comparison with
the structures of four different RT and non-nucleoside inhibitor complexes
reveals that only minor domain rearrangements occur, but there is a significant
repositioning of a three-stranded beta-sheet in the p66 subunit (containing the
catalytic aspartic acid residues 110, 185 and 186) with respect to the rest of
the polymerase site. This suggests that NNIs inhibit RT by locking the
polymerase active site in an inactive conformation, reminiscent of the
conformation observed in the inactive p51 subunit.
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