Structural Insight into Non-Enveloped Virus Binding to Glycosaminoglycan Receptors: A Review

Abstract

Viruses are infectious agents that hijack the host cell machinery in order to replicate and generate progeny. Viral infection is initiated by attachment to host cell receptors, and typical viral receptors are cell-surface-borne molecules such as proteins or glycan structures. Sialylated glycans (glycans bearing sialic acids) and glycosaminoglycans (GAGs) represent major classes of carbohydrate receptors and have been implicated in facilitating viral entry for many viruses. As interactions between viruses and sialic acids have been extensively reviewed in the past, this review provides an overview of the current state of structural knowledge about interactions between non-enveloped human viruses and GAGs. We focus here on adeno-associated viruses, human papilloma viruses (HPVs), and polyomaviruses, as at least some structural information about the interactions of these viruses with GAGs is available. We also discuss the multivalent potential for GAG binding, highlighting the importance of charged interactions and positively charged amino acids at the binding sites, and point out challenges that remain in the field.

Keywords: glycans; glycosaminoglycans; glycovirology; non-enveloped viruses; structural biology; viruses.

Figure 1

AAV-DJ capsid and its binding by GAG (PDB: 5UF6). (a) The viral capsid, with one constituting pentamer highlighted in shades of purple. (b) The viral capsid, with one constituting hexamer, and a threefold symmetry axis peak, highlighted in shades of purple. (c) A close-up of the density (salmon) for the structure at σ 1.5, showing that the capsid protein (purple) matches it closely and can be well resolved, while the ligand (raspberry) density is not visible at this level. (d) The charge distribution in the proximity of the threefold peak. Negatively charged residues are shown in red, positively charged in blue, ligand in wheat. (e) Close-up of the residues identified in mutational studies as contributing to binding HS, highlighted in purple. Capsomers in wheat, pink, and grey. Figures were created using PyMOL [23].

Figure 3

Glycan engagement of BKPyV. (a) Capsid structure of BKPyV (PDB ID 6ESB). The capsid is represented in the gray cartoon, except for the highlighted pentamer, where VP1 monomers are displayed as ribbons in different shades of blue. (b) Top view of BKPyV VP1 pentamers in interaction with GT1b. The pentamer is displayed as a surface colored in different shades of blue for each subunit. The double sialic acid part of GT1b is represented as yellow sticks. (c) Surface representation of BKPyV VP1 pentamers, in blue, associated with the difference map for heparin, in yellow (generated through subtraction of the unliganded VLP map (EMD-3946) from the heparin-VLP map (EMD-3945)). Figures were created using PyMOL [23] and Chimera [51].

Figure 2

Glycan engagement of HPV16. (a) Capsid structure of HPV16 L1 pentamers (PDB ID 5KEP). L1 subunits of one pentamer are displayed in different shades of green. The highlighted pentamer is represented as a ribbon, the remaining capsid is depicted as cartoons. (b) Top view of a HPV16 L1 pentamer (PDB ID 5W1O). Subunits are displayed in cartoon representation and colored in different shades of green. (c) Side view of the pentamer. The heparin ligand is colored by atom type and represented with sticks in yellow. (d) Superposition of HPV16 L1 pentamer in green with its heparin ligand in yellow with HPV18 L1 pentamer (PDB ID 5W1X) in blue and its ligand in cyan. (e) Close-up view of one ligand binding site of HPV16. Ligand-binding residues K356, T358, K361, and K54 are represented as sticks. (f) Close-up view as in (e) of one ligand binding site with the negative F_o–F_c difference map of the ligand contoured at 3σ, colored in red. Figures were created using PyMOL [23].