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Title
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Three-dimensional structures of drug-resistant mutants of human rhinovirus 14.
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Authors
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J.Badger,
S.Krishnaswamy,
M.J.Kremer,
M.A.Oliveira,
M.G.Rossmann,
B.A.Heinz,
R.R.Rueckert,
F.J.Dutko,
M.A.McKinlay.
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Ref.
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J Mol Biol, 1989,
207,
163-174.
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PubMed id
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Abstract
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Mutants of human rhinovirus 14 were isolated and characterized by searching for
resistance to compounds that inhibit viral uncoating. The portions of the RNA
that code for amino acids that surround the antiviral compound binding site were
sequenced. X-ray analysis of two of these mutants, 1188 Val----Leu and 1199
Cys----Tyr, shows that these were single-site substitutions which would
sterically hinder drug binding. Differences in the resistance of mutant viruses
to various antiviral compounds may be rationalized in terms of the
three-dimensional structures of these mutants. Predictions of the structures of
mutant rhinovirus 14 with the substitutions 1188 Val----Leu, 1199 Cys----Tyr and
1199 Cys----Trp in VP1 were made using a molecular dynamics technique. The
predicted structure of the 1199 Cys----Tyr mutant was consistent with the
electron density map, while the 1188 Val----Leu prediction was not. Large (up to
1.4 A) conformational differences between native rhinovirus 14 and the 1199
Cys----Tyr mutant occurred in main-chain atoms near the mutation site. These
changes, as well as the orientation of the 1199 tyrosine side-chain, were
correctly predicted by the molecular dynamics calculation. The structure of the
predicted 1199 Cys----Trp mutation is consistent with the drug-resistant
properties of this virus.
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