The Crystal Structure of Coxsackievirus A21 and Its Interaction with ICAM-1

Abstract

CVA21 and polioviruses both belong to the Enterovirus genus in the family of Picornaviridae, whereas rhinoviruses form a distinct picornavirus genus. Nevertheless, CVA21 and the major group of human rhinoviruses recognize intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, whereas polioviruses use poliovirus receptor. The crystal structure of CVA21 has been determined to 3.2 A resolution. Its structure has greater similarity to poliovirus structures than to other known picornavirus structures. Cryo-electron microscopy (cryo-EM) was used to determine an 8.0 A resolution structure of CVA21 complexed with an ICAM-1 variant, ICAM-1(Kilifi). The cryo-EM map was fitted with the crystal structures of ICAM-1 and CVA21. Significant differences in the structure of CVA21 with respect to the poliovirus structures account for the inability of ICAM-1 to bind polioviruses. The interface between CVA21 and ICAM-1 has shape and electrostatic complementarity with many residues being conserved among those CVAs that bind ICAM-1.

Crystal structure of CD155 and electron microscopic studies of its complexes with polioviruses

“…The calculated area of contact between CD155 and the PV surface is Ϸ1,320 Å 2 (Table S13). In comparison, the area of contact between intercellular adhesion molecule-1 (ICAM-1) and HRVs is only Ϸ900 Å 2 (36,37). The larger surface area used by CD155 in making contacts with PV would require that more surface residues need to be conserved to retain the receptor-binding activity.…”

Interpretation of electron density with stereographic roadmap projections

“…The difference density between the cryo-EM determined structure of the virus/ receptor complex and the crystallographically determined virus structure calculated at the same resolution can be accurately projected onto a roadmap of the virus surface. One example given here is the projection of the density corresponding to the intercellular adhesion molecule-1 (ICAM-1) as seen projected onto the surface residues of the crystallographically determined coxsackievirus A21 (CVA21) structure (Xiao et al, 2005a) (Figure 4C). Another example is a plot of the density at a fixed radius R fix to visualize the position of the "pocket factor" in CVA21 (Xiao et al, 2005a).…”

“…One example given here is the projection of the density corresponding to the intercellular adhesion molecule-1 (ICAM-1) as seen projected onto the surface residues of the crystallographically determined coxsackievirus A21 (CVA21) structure (Xiao et al, 2005a) (Figure 4C). Another example is a plot of the density at a fixed radius R fix to visualize the position of the "pocket factor" in CVA21 (Xiao et al, 2005a). This factor is a fatty acid-like molecule that is bound into a pocket immediately below the floor of the canyon, critical to the stability of the virion (Rossmann et al, 2002) (Figure 4B).…”

“…B. The location of the "pocket factor" in a 3.2 Å resolution electron density map of CVA21 crystal (Xiao et al, 2005a) shown as a spherical section at a fixed radius (R fix = 129.6 Å) is outlined in black based on the coordinates of a myristate molecule that was fitted to the density. C. The footprint of ICAM-1 onto the CVA21 surface.…”

“…Examples include studies of various viruses Böttcher et al, 1997b;Conway et al, 1997;Leiman et al, 2004;Morais et al, 2005;Zhou et al, 2000), virus/receptor complexes (Belnap et al, 2000;Bubeck et al, 2005;Hewat et al, 2000;Rossmann et al, 2002;Xiao et al, 2005a), many important cellular complexes such as ribosomes (Allen et al, 2005;Matadeen et al, 1999), nuclear pores (Beck et al, 2004), bacterial flagella (Yonekura et al, 2005), GroEL , membrane Ca 2+ channels (Serysheva et al, 2005), ATPases (Bernal and Stock, 2004;Chen et al, 2004), and many large protein complexes (Acehan et al, 2002;Cheng et al, 2004;Ishikawa et al, 2004;Zhou et al, 2001). Cryo-EM has significantly improved in the last ten years to achieve sub-nanometer resolution, where secondary structural features become visible (Böttcher et al, 1997b;Conway et al, 1997;van Heel et al, 2000;Zhou et al, 2000).…”