Virus structure
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Hemagglutinin (HA) is an antigenic glycoprotein, which is placed on the surface of the influenza viruses. It is responsible for binding the virus to the host cell, that is being infected. The name „hemagglutinin“ comes from the ability of protein to cause erythrocytes to agglutinate („clump together“). The process is like this: Hemagglutinin (HA) binds to the monosaccharide sialic acid which is present on the surface of its target host cells. The cell membrane then engulfs the virus through endocytosis and followed by formation of endosome. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome. When the pH decrease to 6.0, the HA molecule becomes partially unfold, and release a hydrophobic portion of peptide chain that was previously hidden. This so-called „fusion peptide“ acts like a molecular grapple hook for lock on the endosomal membrane. The rest of the HA molecule refolds into a new structure and pulls the endosomal membrane right up next to the viral membrane, causing the two to fuse together. When it happened, the viral RNA genome enters into the cell‘s cytoplasm.
To find an effective drug for Zika virus, it is important to understand how numerous proteins which are critical for the virus' structure and function interact with their counterparts. One approach to inhibiting the flavivirus is to deter its ability to bind onto glycoproteins; however, the crystal structures of envelope proteins of the ever-evolving viral strains that decipher glycosidic or drug-molecular interactions are not always available. To fill this gap, we are reporting a holistic, simulation-based approach to predict compounds that will inhibit ligand binding onto a structurally unresolved protein, in this case the Zika virus envelope protein (ZVEP), by developing a three-dimensional general structure and analyzing sites at which ligands and small drug-like molecules interact. By examining how glycan molecules and small-molecule probes interact with a freshly resolved ZVEP homology model, we report the susceptibility of ZVEP to inhibition via two small molecules, ZINC33683341 and ZINC49605556-by preferentially binding onto the primary receptor responsible for the virus' virulence. Antiviral activity was confirmed when ZINC33683341 was tested in cell culture. We anticipate the results to be a starting point for drug discovery targeting Zika virus and other emerging pathogens.
- MeSH
- antivirové látky chemie farmakologie MeSH
- Cercopithecus aethiops MeSH
- knihovny malých molekul chemie farmakologie MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- polysacharidy metabolismus MeSH
- proteiny virového obalu antagonisté a inhibitory chemie MeSH
- strukturní homologie proteinů MeSH
- vazebná místa MeSH
- Vero buňky MeSH
- virová nálož účinky léků MeSH
- virus zika účinky léků metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
UNLABELLED: The pollination services provided by the western honeybee (Apis mellifera) are critical for agricultural production and the diversity of wild flowering plants. However, honeybees suffer from environmental pollution, habitat loss, and pathogens, including viruses that can cause fatal diseases. Israeli acute bee paralysis virus (IAPV), from the family Dicistroviridae, has been shown to cause colony collapse disorder in the United States. Here, we present the IAPV virion structure determined to a resolution of 4.0 Å and the structure of a pentamer of capsid protein protomers at a resolution of 2.7 Å. IAPV has major capsid proteins VP1 and VP3 with noncanonical jellyroll β-barrel folds composed of only seven instead of eight β-strands, as is the rule for proteins of other viruses with the same fold. The maturation of dicistroviruses is connected to the cleavage of precursor capsid protein VP0 into subunits VP3 and VP4. We show that a putative catalytic site formed by the residues Asp-Asp-Phe of VP1 is optimally positioned to perform the cleavage. Furthermore, unlike many picornaviruses, IAPV does not contain a hydrophobic pocket in capsid protein VP1 that could be targeted by capsid-binding antiviral compounds. IMPORTANCE: Honeybee pollination is required for agricultural production and to sustain the biodiversity of wild flora. However, honeybee populations in Europe and North America are under pressure from pathogens, including viruses that cause colony losses. Viruses from the family Dicistroviridae can cause honeybee infections that are lethal, not only to individual honeybees, but to whole colonies. Here, we present the virion structure of an Aparavirus, Israeli acute bee paralysis virus (IAPV), a member of a complex of closely related viruses that are distributed worldwide. IAPV exhibits unique structural features not observed in other picorna-like viruses. Capsid protein VP1 of IAPV does not contain a hydrophobic pocket, implying that capsid-binding antiviral compounds that can prevent the replication of vertebrate picornaviruses may be ineffective against honeybee virus infections.
- MeSH
- Dicistroviridae ultrastruktura MeSH
- konformace proteinů MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- včely virologie MeSH
- virion ultrastruktura MeSH
- virové plášťové proteiny chemie metabolismus MeSH
- virové struktury * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
