title: Structural analysis of antiviral agents that interact with the capsid of human rhinoviruses.
abstract: X-Ray diffraction data have been obtained for nine related antiviral agents ("WIN compounds") while bound to human rhinovirus 14 (HRV14). These compounds can inhibit both viral attachment to host cells and uncoating. To calculate interpretable electron density maps it was necessary to account for (1) the low (approximately 60%) occupancies of these compounds in the crystal, (2) the large (up to 7.9 A) conformational changes induced at the attachment site, and (3) the incomplete diffraction data. Application of a density difference map technique, which exploits the 20-fold noncrystallographic redundancy in HRV14, resulted in clear images of the HRV14:WIN complexes. A real-space refinement procedure was used to fit atomic models to these maps. The binding site of WIN compounds in HRV14 is a hydrophobic pocket composed mainly from residues that form the beta-barrel of VP1. Among rhinoviruses, the residues associated with the binding pocket are far more conserved than external residues and are mostly contained within regular secondary structural elements. Molecular dynamics simulations of three HRV14:WIN complexes suggest that portions of the WIN compounds and viral protein near the entrance of the binding pocket are more flexible than portions deeper within the beta-barrel.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: J
authors.initials: J
authors.lastname: Badger
authors.forename: I
authors.initials: I
authors.lastname: Minor
authors.forename: M A
authors.initials: MA
authors.lastname: Oliveira
authors.forename: T J
authors.initials: TJ
authors.lastname: Smith
authors.forename: M G
authors.initials: MG
authors.lastname: Rossmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D002213:Capsid / Q000187:drug effects* / Q000648:ultrastructure; D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000998:Antiviral Agents