title: Three-dimensional structures of drug-resistant mutants of human rhinovirus 14.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907.
authors.forename: J
authors.initials: J
authors.lastname: Badger
authors.forename: S
authors.initials: S
authors.lastname: Krishnaswamy
authors.forename: M J
authors.initials: MJ
authors.lastname: Kremer
authors.forename: M A
authors.initials: MA
authors.lastname: Oliveira
authors.forename: M G
authors.initials: MG
authors.lastname: Rossmann
authors.forename: B A
authors.initials: BA
authors.lastname: Heinz
authors.forename: R R
authors.initials: RR
authors.lastname: Rueckert
authors.forename: F J
authors.initials: FJ
authors.lastname: Dutko
authors.forename: M A
authors.initials: MA
authors.lastname: McKinlay
mesh_terms: D002869:Chromosome Aberrations; D004352:Drug Resistance, Microbial; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D012229:Rhinovirus; D014961:X-Ray Diffraction
chemical_list: D046911:Macromolecular Substances