Structure of Seneca Valley Virus-001: an oncolytic picornavirus representing a new genus

Abstract

The crystal structure of Seneca Valley Virus-001 (SVV-001), the representative member of a new genus, Senecavirus, is reported at 2.3A resolution. SVV-001 is the first naturally occurring nonpathogenic picornavirus shown to mediate selective cytotoxicity towards tumor cells with neuroendocrine cancer features. The nonsegmented (+) ssRNA genome of SVV-001 shares closest sequence similarity with the genomes of the members of Cardiovirus. The overall tertiary structure of VP1-VP4 subunits is conserved with the exception of loops, especially those of VP1 that show large deviations relative to the members of the cardioviruses. The surface loops of VP1 and VP2 are predicted to mediate cell tropism of SVV-001. In addition, the organization of the packaged nucleic acid density indicates that certain regions of VP2 and VP4 interact closely with the packaged nucleic acid.

Figure 1

Protomer structure and the quality of the electron density map of SVV-001. Ribbon diagrams of SVV-001 protomer, (a) front view and (b) a side view, highlighting the different subunits and the prominent surface loops. VP1, VP2, VP3 and VP4 subunits are shown in blue, green, red and yellow respectively. (c) Stereo diagram showing the quality of the NCS averaged electron density map at 2.3Å resolution, contoured at 1.2σ.

Figure 2

Structural comparison of SVV-001 and MEV capsids: (a) Surface rendered illustrations of (a) SVV-001 and (b) MEV capsid highlighting the differences of their surfaces, generated using the program TexMol (Bajaj et al., 2004). A coloring scheme of blue to yellow was used as a function of the distance from the centre of the virus. The blue regions represent the depressions while the yellow regions represent the elevations on the surface. Ribbon diagrams of the superposition of (c) VP1, (d) VP2 and (e) VP3 subunits of MEV (Magenta) onto the corresponding subunits of SVV-001 (Blue). Corresponding loops showing maximum structural differences are highlighted by arrows.

Figure 3

An illustration of nucleic acid organization in SVV-001 at 20Å resolution. a) A view down the particle 2-fold axis showing the bulk RNA density (orange) and part of the protein shell. b) A side view of the same.

Figure 4

Locations of putative receptor binding sites on SVV-001. (a) Positions of major receptor binding motifs on the surface of SVV-001. Sites numbered 1 and 2 indicate the locations of the DGK and the LDV motif while K229 is numbered 3. The LDV motif (site 2) is hidden under the DGK motif (site 1) and is indicated by an arrow. The icosahedral asymmetric unit comprising VP1-4 is indicated by a trapezoid. (b) Enlarged view of the icosahedral asymmetric unit oriented to highlight the positions of DGK, LDV and K229. (c) The superposition of DGK motif (gold) on the RGD motif (cyan). (c) Location of the LDV motif, shown as purple surface and stick diagram, in the VP2 subunit. (d) Structural superposition of loop containing K229 (VP1) of SVV-001 (pink) onto LDL binding loop of HRV2. The structural proximity of K229 of SVV-001 with the critical residue, K224 of HRV2 in the HRV2-LDL receptor (baize colored surface) complex, indicates that it might play a similar role in binding to the LDL receptor in SVV-001.