HUMAN RHINOVIRUS-3 AT 3.0-ANGSTROM RESOLUTION

Background: The over 100 serotypes of human rhinoviruses (HRV) are maj or causative agents of the common cold in humans. These HRVs can be ro ughly divided into a major and minor group according to their cellular receptors. They can also be divided into two antiviral groups, A and B, based on their sensitivity to different capsid-binding antiviral co mpounds. The crystal structures of HRV14 and HRV16, major-receptor gro up rhinoviruses, as well as HRV1A, a minor-receptor group rhinovirus, were determined previously. Sequence comparisons had shown that HRV14 seemed to be an outlier among rhinoviruses. Furthermore, HRV14 was the only virus with no cellular 'pocket factor' in a hydrophobic pocket w hich is targeted by many capsid-binding antiviral compounds and is tho ught to regulate viral stability, HRV3, another major-receptor group v irus, was chosen for study because it is one of a subset of serotypes that best represents the drug sensitivity of most rhinovirus serotypes , Both HRV3 and HRV14 belong to antiviral group A, while HRV16 and HRV 1A belong to antiviral group B. Results: Surprisingly, HRV3 was found to be very similar to HRV14 in sequence and structure. Like HRV14, cry stallized HRV3 also has no bound pocket factor, The structure of HRV3 complexed with an antiviral compound, WIN56291, was also determined an d found to be similar to the same antiviral compound complexed with HR V14. Conclusions: The amino-acid sequence and structural similarity be tween HRV3 and HRV14 suggests that rhinoviruses in the same antiviral group have similar amino-acid sequences and structures. The similar am ino-acid composition in the pocket region and the viral protein VP1 N termini in all known group B HRV sequences suggests that these viruses may all contain pocket factors and ordered N-terminal amphipathic hel ices in VP1. Both of these factors contribute to viral stability, whic h is consistent with the observations that group B rhinoviruses have a higher chance of successful transmission from one host to another and is a possible explanation for the observed higher pathogenicity of th ese rhinoviruses.