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PDBsum entry 1b9t
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site.
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Authors
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J.B.Finley,
V.R.Atigadda,
F.Duarte,
J.J.Zhao,
W.J.Brouillette,
G.M.Air,
M.Luo.
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Ref.
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J Mol Biol, 1999,
293,
1107-1119.
[DOI no: ]
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PubMed id
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Abstract
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The active site of type A or B influenza virus neuraminidase is composed of 11
conserved residues that directly interact with the substrate, sialic acid. An
aromatic benzene ring has been used to replace the pyranose of sialic acid in
our design of novel neuraminidase inhibitors. A bis(hydroxymethyl)pyrrolidinone
ring was constructed in place of the N-acetyl group on the sialic acid. The
hydroxymethyl groups replace two active site water molecules, which resulted in
the high affinity of the nanomolar inhibitors. However, these inhibitors have
greater potency for type A influenza virus than for type B influenza virus. To
resolve the differences, we determined the X-ray crystal structure of three
benzoic acid substituted inhibitors bound to the active site of B/Lee/40
neuraminidase. The investigation of a hydrophobic aliphatic group and a
hydrophilic guanidino group on the aromatic inhibitors shows changes in the
interaction with the active site residue Glu275. The results provide an
explanation for the difference in efficacy of these inhibitors against types A
and B viruses, even though the 11 active site residues of the neuraminidase are
conserved.
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Figure 3.
Figure 3. Comparison of the pyrrolidinone ring conformation and interactions of the hydroxymethyl groups with
the NA active site. (a) BANA205, (b) BANA206. In (a), the pyrrolidinone ring is nearly flat, while in (b) the ring is
puckered. The puckering difference allows the hydroxymethyl groups to interact differently with NA residues. Active
site residues are indicated.
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Figure 4.
Figure 4. Overlay of the com-
plexes of BANA205 and BANA206
with B/Lee/40 NA, and native B/
Lee/40 NA showing water del-
etions and movements, as well as
the movement of the Glu275 side-
chain. Blue is native B/Lee/40 NA,
red is B/Lee/40 NA complexed
with BANA206, and green is B/
Lee/40 NA complexed with
BANA205. The pyrrolidinone ring
and the two hydroxymethyl groups
replace water molecules WAT677,
WAT725 and WAT723. The
induced rotation of Glu275 by the
inhibitor molecules is shown.
Movement of WAT724 is shown by
the arrow and it is pushed
~1.4
Å
deeper into the binding pocket. In
the case of BANA206, WAT724
does not move because the rotation
of Glu275 supplies WAT724 with a
new hydrogen bond to compensate
for the lost hydrogen bond from
the missing WAT723 (Figure 5(b)).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1999,
293,
1107-1119)
copyright 1999.
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