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Title
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A comparison of the anti-rhinoviral drug binding pocket in HRV14 and HRV1A.
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Authors
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K.H.Kim,
P.Willingmann,
Z.X.Gong,
M.J.Kremer,
M.S.Chapman,
I.Minor,
M.A.Oliveira,
M.G.Rossmann,
K.Andries,
G.D.Diana.
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Ref.
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J Mol Biol, 1993,
230,
206-227.
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PubMed id
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Abstract
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The three-dimensional structures of two human rhinovirus serotypes (HRV14 and
HRV1A) are compared when complexed with various antiviral agents. Although these
agents all bind into the same hydrophobic pocket, the exact viral-drug
interactions differ. In the absence of drugs, the pocket is occupied by a fatty
acid in HRV1A, but is empty in HRV14 except for two water molecules. The
conformation of each drug is dependent upon the shape of the hydrophobic pocket.
In HRV14 the major residues determining the shape of the binding site are Y1128,
P1174 and M1224, corresponding to I1125, M1169 and I1220 in HRV1A. When there is
no cofactor or a drug in the pocket, the entrance to the pocket is open.
However, the entrance is closed when the pocket is occupied by a cofactor or a
drug. There are relatively small conformational changes when the agents displace
the natural cofactor in HRV1A. In contrast, there are much larger conformational
changes on binding a drug in HRV14. These differences cause an inhibition of
viral attachment in HRV14 but not in HRV1A. Binding of the drugs results in
three additional interprotomer hydrogen bonds in HRV14 and one in HRV1A. These
hydrogen bonds and a potential loss of flexibility upon efficient packing of the
pocket may contribute to the inhibition of uncoating in both serotypes.
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