Global displacement of canine parvovirus by a host-adapted variant: structural comparison between pandemic viruses with distinct host ranges

Abstract

Canine parvovirus type 2 (CPV-2) emerged in 1978 and spread worldwide within 2 years. Subsequently, CPV-2 was completely replaced by the variant CPV-2a, which is characterized by four specific capsid (VP2) mutations. The X-ray crystal structure of the CPV-2a capsid shows that each mutation confers small local changes. The loss of a hydrogen bond and introduction of a glycine residue likely introduce flexibility to sites that control interactions with the host receptor, antibodies, and sialic acids.

FIG 1

(A) The crystal structure of a single capsid protein of CPV-2a shown as a ribbon diagram. The CPV-2a and CPV-2 (PDB code 1C8D) (25) carbon alphas superimposed with a root mean square deviation (RMSD) of 0.546 Å. Symmetry axes are indicated by black lines and symbols. (B) A representative region of the 2mFo-dFc electron density map of CPV-2a rendered at 1.0 σ shows the quality of the map with the crystal structure (green and red). (C to H) The local structure of each altered residue (cyan and yellow for CPV-2a and CPV-2, respectively) is shown with the superimposed structures of CPV-2a and CPV-2 (blue and gold, respectively) (PDB code 1C8D) (25) within the electron density to show side chain density.

FIG 2

Zoomed-in view of the GH loop in the structures of CPV-2 (gold) compared to CPV-2a (blue) to show the substitution at position 300 (red arrows) from Ala (yellow in CPV-2) to Gly (cyan in CPV-2a). The ribbon diagram displays hydrogen bonds (green) and shows that the A300G change in CPV-2a results in the loss of a hydrogen bond (black arrow). The correspondingly higher B-factor in the GH loop of CPV-2a suggests enhanced flexibility.

FIG 3

(A) Capsid protein mutations that differentiate CPV-2 and CPV-2a, including VP2 residues 87, 300, and 305 (highlighted in yellow), map to the surface of virus, which is displayed as a stereographic projection with the surface residues represented as a quilt of amino acids with one icosahedral asymmetric unit outlined by the triangle (26). The site of the VP2 426 mutation that distinguishes different variants of CPV-2a (i.e., CPV-2b and -2c) is also highlighted in yellow and is located on the top of the 3-fold spike. VP2 residue 101 is buried just beneath the surface. Individual capsid proteins are differentiated by shades of blue, magenta, and green to show the close-knit interactions that make up the capsid. (B) The stacking interaction of residues 87 and 101 (pink and yellow) with residues 300 and 305 (magenta and yellow) on a neighboring VP2 molecule is possible because the structural proteins comprising the icosahedral capsid intertwine.