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PDBsum entry 3kk3
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Transferase/DNA
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PDB id
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3kk3
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References listed in PDB file
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Key reference
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Title
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Visualizing the molecular interactions of a nucleotide analog, Gs-9148, With HIV-1 reverse transcriptase-Dna complex.
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Authors
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E.B.Lansdon,
D.Samuel,
L.Lagpacan,
K.M.Brendza,
K.L.White,
M.Hung,
X.Liu,
C.G.Boojamra,
R.L.Mackman,
T.Cihlar,
A.S.Ray,
M.E.Mcgrath,
S.Swaminathan.
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Ref.
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J Mol Biol, 2010,
397,
967-978.
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PubMed id
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Abstract
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GS-9148
([5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic
acid) is a dAMP (2'-deoxyadenosine monophosphate) analog that maintains its
antiviral activity against drug-resistant HIV. Crystal structures for HIV-1
reverse transcriptase (RT) bound to double-stranded DNA, ternary complexes with
either GS-9148-diphosphate or 2'-deoxyadenosine triphosphate (dATP), and a
post-incorporation structure with GS-9148 translocated to the priming site were
obtained to gain insight into the mechanism of RT inhibition. The binding of
either GS-9148-diphosphate or dATP to the binary RT-DNA complex resulted in the
fingers subdomain closing around the incoming substrate. This produced up to a 9
A shift in the tips of the fingers subdomain as it closed toward the palm and
thumb subdomains. GS-9148-diphosphate shows a similar binding mode as dATP in
the nucleotide-binding site. Residues whose mutations confer resistance to
nucleotide/nucleoside RT inhibitors, such as M184, Y115, L74, and K65, show
little to no shift in orientation whether GS-9148-diphosphate or dATP is bound.
One difference observed in binding is the position of the central ring. The
dihydrofuran ring of GS-9148-diphosphate interacts with the aromatic side chain
of Y115 more than does the ribose ring of dATP, possibly picking up a favorable
pi-pi interaction. The ability of GS-9148-diphosphate to mimic the active-site
contacts of dATP may explain its effective inhibition of RT and maintained
activity against resistance mutations. Interestingly, the 2'-fluoro moiety of
GS-9148-diphosphate was found in close proximity to the Q151 side chain,
potentially explaining the observed moderately reduced susceptibly to GS-9148
conferred by Q151M mutation.
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