Rhinovirus capsid

In 1985 Dr. Michael Rossmann and his colleagues determined for the first time the three-dimensional structure of a human rhinovirus [15], Their studies, performed with human rhinovirus type 14 (HRV-14), revealed the structure as an eicosahedron consisting of four proteins designated VP1, VP2, VP3, and VP4 forming a protomeric unit, combined to form a fivefold axis of symmetry (Fig. 2). The surface of the capsid... 

Fox MP, McKinlay MA, Diana GD, Dutko FJ. Binding affinities of structurally related human rhinovirus capsid binding compounds are related to their activities against human rhinovirus type 14. Antimicrob Agents Chemother 1991 30 110-116. 

Rhinoviruses cause the common cold. In these viruses, the capsid is shaped like an icosahedron—1. e., an object made up of 20 equilateral triangles. Its surface is formed from three different proteins, which associate with one an-... 

It took the short time of one year or so to solve the structure of rhinovirus which causes the common cold. This relied on two major advances in methods. The first was the use of synchrotron radiation in data collection. Nearly a million reflections were collected on the protein crystallography facility at the Cornell Synchrotron source in a matter of days. This conveyed a speed advantage over data collection on a conventional source and also ameliorated an otherwise impossible problem of radiation damage when long exposure times were used. The far greater rate of radiation damage in the X-ray beam in relation to plant viruses is symptomatic of an inherently less stable protein capsid and the absence of quasi-symmetry. The capsid consists of 60 copies each of four proteins and the virus with about 30 % RNA has a total molecular weight of about 8.5 million. 

Tipranavir, a VIH-PR inhibitor, was launched for AIDS therapy (Figure 8.12). Pleconaril inhibits adhesion by binding the viral capsid. It is currently being evaluated for viral infections of the respiratory tract, in particular, for picornavims (meningitis) and rhinovirus (colds) (Figure 8.12). 

Schematic illustration of the icosahedral rhinovirus 14. (a) Shown is the icosahedron comprised of 60 copies each of VP1 (light gray), VP2 (black), and VP3 (gray). The shaded circles around each five-fold axis indicate the canyon positions. Also indicated is the approximate position of the VP1 hydrophobic pocket that lies underneath the surface of the virion, (b) An icosahedral pentamer is expanded with one viral protomer shown as a protein ribbon diagram, (c) This pentamer is seen in a cutaway view. Here VP1 is white, VP2 and VP4 black, and VP3 gray. A capsid-binding compound is depicted as black spheres inside the VP1 ribbon diagram. The cross hatched regions on the (c) schematic (right) indicate areas that disorder when HRV14 crystals are exposed to acid.

Ninomiya Y, Shimma N, Ishitsuka H. Comparative studies on the antirhino virus activity and mode of action of the rhinovirus capsid binding agents, chalcone amides. Antivir Res 1990 13 61-74. 

The capsid is composed of 60 copies of three classic jelly-roU j3 barrels (VPl, VP2, and VPS), and a small VP4 on the inside surface of the capsid. The proteins vary in length, between about 230 and 300 amino acids. The corresponding proteins of different viruses are more similar to one another than are VP1-VP3 within one species (Rossmann, 1987). VPl and VPS have N-terminal extensions to the barrel that meander away to form contacts with neighboring subunits (Hogle et al, 1985 Rossmann et al, 1985). The VP2 extension forms an additional j3 ribbon on the RNA side of the capsid. Various secondary structural elements are inserted within the loops. Like SBMV, there is a helix in the CD loops of all of the capsid proteins of poliovirus, rhinovirus, and so on. In the picornavimses there is a short helix either breaking or preceding /3B. 

FMDV is the outlier of picornavirus structures (Fry et al, 1990), with capsid proteins that are 20% shorter than in the other viruses. The VPl loops near the 5-fold axis are sheared off, so that there is not the pronounced 5-fold protrusion and canyon of rhinoviruses and polioviruses (Acharya et al, 1989). This leaves a longer VPl GH loop as the prominent surface feature, which is highly antigenic, the site of the RGD receptor attachment sequence, but disordered in structure unless a disulfide is reduced (Acharya et al, 1989 Fox et al, 1989 Lea et al, 1994 Rowlands et al, 1994). FMDV VP2 is more similar to its homologs, except that the GH loop puff is 50 residues shorter than in poliovirus, and its space is occupied pardy by the longer VPl GH loop. 

The structure of poliovirus is remarkably similar to that of human rhinovirus 14 [27, 46]. It is composed of three major viral proteins (VPl-VP3), with each forming a single canonical viral j3 barrel. VP4 lies at the interface between the capsid and the interior RNA. Poliovirus uses CD155... 

In the first studies, antibodies were used to elucidate the dynamic nature of poliovirus [51]. Antibodies were raised against peptides representing VP4 and the N termini of VPl. In the crystal structures of all of the picornaviruses, these termini lie at the capsid-RNA interface and are therefore not exposed to external solvent [27, 46, 52-55]. These antibodies bound to the virus when the particles were heated to 37°C but did not bind when added to virus at room temperature or when the virus was heated to 37°G and then cooled to room temperature. Therefore, although difficult to visualize with the static structure of the capsid, the only explanation for these results is that these buried termini are transiently exposed. This exposure is facilitated by higher temperatures and was proposed to be part of the normal infection process. This idea of dynamic capsid structures was subsequently supported by mass spectroscopy analysis of flock house virus [56] and rhinovirus [57] and by a series of drug—poliovirus structures [58]. 

Tormo, J., Blaas, D., Parry, N. R., Rowlands, D., Stuart, D., and Fita, 1. (1994). Crystal structure of a human rhinovirus neutralizing antibody complexed with a peptide derived from viral capsid protein VP2. EMBO J. 13, 2247-2256. 

Figure 10.17. Structure of rhinovirus capsid protein VPl showing the bound conformation of antiviral isoxa-zole compounds (78) [dis-oxaril, WIN-51711 panel a, top], (79) [WIN-54954 panel b, middle], and (80) [ple-conaril, WIN-63843 panel c, bottom]. The PDB codes for the X-ray structural model coordinates used to create these views are IPIV (for 78), 2HWE(for 79), and 1C8M (for 80). On the left side of each panel, the inhibitors are shown as van der Waals surfaces, and the protein as a ribbon diagram. On the right side, the structures of the inhibitor alone are shown, from the same view, as ball and stick representations.

Human rhinovirus coat protein Common cold Attachment to host cell receptor, viral entry, and uncoating Binding in hydrophobic pocket (capsid stabilization)... 

A confirmation of the alkyl oxime ether as metabolically stable isoster of an ester has been reported by Watson et al. in the synthesis of a capsid binder active against Human Rhinovirus (Figure 15.30). 

The complete, mature virus particle is known as a virion and usually has a regular shape. Many virions are icosahedral, that is, the capsid is formed from identical protein subunits (capsomeres) that combine to produce a solid with twenty faces, each of which is an equilateral triangle. The herpes viruses are of this type, as are the picomaviruses of which the polio viruses and rhinoviruses (cold viruses) are the bestknown members. The other common regular shape is that of a helix, and the tobacco mosaic virus is of this type. Its single helical strand of RNA is enclosed within a hollow tube, which comprises 2130 protein subunits arranged in a helix. Other viruses with a similar structure are the... 

Rhinoviruses belong to the picornaviridae family small icosahedral viruses with an average diameter of 300 A and a molecular mass of approximately 8.5 X 10 Da. Like all picornaviruses, HRVs are made of a protein capsid that encases a single-stranded, positive-sense RNA molecule of about 7000 bases. The capsid is built from 60 copies of viral proteins 1, 2, 3 and 4 (VPl, VP2, VP3, and VP4). VPl, VP2 and VP3 assemble on the exterior to form the protein shell, and VP4 resides in the interior of the capsid,... 

The capsid. The capsid of the rhinovirus is encapsulated between two triacontahe-dra one enclosing the external surface of the capsid and one delimiting the central hole. The two polyhedra are related through a radial scaling Sj with scaling factor T, as shown in Figure 11-8. 

Accordingly, all vertices of the molecular form encapsulating the capsid of the rhinovirus are at points of the same icosahedral lattice, proving that the icosahedral lattice is indeed the form lattice for the viral capsid, which has its envelope and hole related by a three-dimensional crystallographic scaling. This property provides an answer to the first question. 

Figure 11-8. The capsid of the human rhinovirus is enc sulated between two ico-dodecahedra, one external and one internal scaled with a factor 1/r, with r the golden ratio. All vertices belong to the same icosahedral lattice. Only the vertices and the monomeric chains of the four coat proteins VPl, VP2, VP3 and VP4 in die various equatorial regions are plotted in projected views along the fivefold, the twofold and die direefold axes, respectively (adapted from [27], courtesy lUCr)...

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