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PDBsum entry 1vrh
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273 a.a.
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255 a.a.
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236 a.a.
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40 a.a.
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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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Synthesis and activity of piperazine-Containing antirhinoviral agents and crystal structure of sdz 880-061 bound to human rhinovirus 14.
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Authors
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D.A.Oren,
A.Zhang,
H.Nesvadba,
B.Rosenwirth,
E.Arnold.
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Ref.
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J Mol Biol, 1996,
259,
120-134.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
96%.
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Abstract
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A series of antipicornaviral agents containing piperazinyl moieties was
synthesized with the objective of obtaining a compound with a broad spectrum of
antirhinovirus activity, high potency (< or = 0.003 microgram/ml), and low
cytotoxicity (> or = 30 micrograms/ml). Five compounds of this series were
evaluated in detail for efficacy against various HRV serotypes. The agent SDZ
880-061, containing the benzothiazine moiety SDZ 108-075, which is particularly
active against HRV14, and the thiazolyl acetic acid ester group of SDZ 89-124,
which is potent against HRV1B, indeed has a relatively broad antiviral spectrum.
SDZ 880-061 inhibited 85% of 89 HRV serotypes tested at a concentration of <
or = 3 micrograms/ml. The 3.0 A resolution X-ray structure of SDZ 880-061 bound
to HRV14 has revealed the binding characteristics of this potent compound. It
binds in the same pocket as other capsid-binding antiviral agents characterized
to date, leaving the innermost portion of the pocket vacant. The binding causes
similar, although less extensive, alterations of the HRV14 VP1 backbone
conformation (residues 100 to 110, 151 to 159, and 213 to 224) compared to other
antiviral agents analyzed structurally. Although the contacts between SDZ
880-061 and HRV14 are mostly of hydrophobic character, the inhibitor has three
relatively short polar interactions with residues of VP1 that represent
potential hydrogen bonds. The amount of solvent-accessible surface area of SDZ
880-061 buried in the complex (613 A2) is within the range of that observed in
protein-protein interfaces. The observed influence of time of addition or
removal of SDZ 880-061 on virus yield and on the infectious-center formation
indicates that the compound primarily interferes with HRV14 cellular attachment.
Since it is assumed that uncoating requires virion instability and/or
flexibility, the finding that SDZ 880-061 has only a marginal effect on
uncoating may be due to the fact that it does not completely fill the
hydrophobic pocket.
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Figure 2.
Figure 2. Stereoview of the electron density in the region of the antiviral binding pocket. The map is calculated using
the native phases and coefficients of kFnative - (1 - k)Fcomplex (k = 0.65) contoured at 2s. SDZ 880-061 is modeled into the
density as described in the text. The vacant region in the hydrophobic binding pocket is shown. Note the lack of density
for solvent molecules in this region. We suggest that this vacancy allows virion uncoating, hence the limited activity
of SDZ 880-061 during stages post-adsorption.
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Figure 3.
Figure 3. The benzothiazine ring of SDZ 880-061 is
situated between Val188 and Ile104 of VP1. These VP1
residues are displayed in CPK form to highlight the
volume they occupy. There is little room for an additional
carbon group on either of these residues which might be
contributing to the increased activity of SDZ 880--061
against serotypes 14 and 89 (Table 6).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1996,
259,
120-134)
copyright 1996.
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Secondary reference #1
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Title
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Sdz 35-682, A new picornavirus capsid-Binding agent with potent antiviral activity.
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Authors
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B.Rosenwirth,
D.A.Oren,
E.Arnold,
Z.L.Kis,
H.J.Eggers.
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Ref.
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Antiviral Res, 1995,
26,
65-82.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Structure determination of antiviral compound sch 38057 complexed with human rhinovirus 14.
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Authors
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A.Zhang,
R.G.Nanni,
T.Li,
G.F.Arnold,
D.A.Oren,
A.Jacobo-Molina,
R.L.Williams,
G.Kamer,
D.A.Rubenstein,
Y.Li.
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Ref.
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J Mol Biol, 1993,
230,
857-867.
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PubMed id
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Secondary reference #3
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Title
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Three-Dimensional structure-Activity relationships for antiviral agents that interact with picornavirus capsids
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Authors
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A.Zhang,
R.G.Nanni,
D.A.Oren,
E.J.Rozhon,
E.Arnold.
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Ref.
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semin virol, 1992,
3,
453.
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Secondary reference #4
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Title
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Analysis of the structure of a common cold virus, Human rhinovirus 14, Refined at a resolution of 3.0 a.
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Authors
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E.Arnold,
M.G.Rossmann.
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Ref.
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J Mol Biol, 1990,
211,
763-801.
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PubMed id
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Secondary reference #5
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Title
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The use of molecular-Replacement phases for the refinement of the human rhinovirus 14 structure.
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Authors
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E.Arnold,
M.G.Rossmann.
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Ref.
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Acta Crystallogr A, 1988,
44,
270-282.
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PubMed id
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Secondary reference #6
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Title
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Structure of a human common cold virus and functional relationship to other picornaviruses.
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Authors
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M.G.Rossmann,
E.Arnold,
J.W.Erickson,
E.A.Frankenberger,
J.P.Griffith,
H.J.Hecht,
J.E.Johnson,
G.Kamer,
M.Luo,
A.G.Mosser.
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Ref.
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Nature, 1985,
317,
145-153.
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PubMed id
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