STRUCTURE OF POLIOVIRUS TYPE-2 LANSING COMPLEXED WITH ANTIVIRAL AGENTSCH48973 - COMPARISON OF THE STRUCTURAL AND BIOLOGICAL PROPERTIES OF THE 3 POLIOVIRUS SEROTYPES

Background: Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA vir uses, which belong to the picornavirus family,and occur as three disti nct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 an d a type 3 poliovirus are already known. Structural studies of poliovi rus type 2 Lansing (PV2L) were initiated to try to enhance our underst anding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus. Results: The crystal structure of the mouse neurovirulent PV2L complexed with a po tent antiviral agent, SCH48973, was determined at 2.9 Angstrom resolut ion. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VPI that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known s tructures of enteroviruses, the entire polypeptide chain of PV2L VP4 i s visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The bro ad-spectrum antiviral agent SCH48973 is observed binding in a pocket w ithin the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predomin antly hydrophobic interactions with the pocket residues. Conclusions: Some of the conformational changes required for infectivity and involv ed in the control of capsid stability and neurovirulence in mice may o ccur in the vicinity of the fivefold axis of the poliovirus, where the re are significant structural differences among the three poliovirus s erotypes in the surface exposed loops of VPI (BC, DE, and HI), A surfa ce depression is located at the fivefold axis of PV2L that is not pres ent in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately lea ds to the loss of Viral RNA. A model is proposed that suggests dual in volvement of the Virion fivefold and pseudo-threefold axes in receptor -mediated initiation of infection by picornaviruses.