6jhs: Difference between revisions
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The | ==The cryo-EM structure of HAV bound to a neutralizing antibody-F7== | ||
<StructureSection load='6jhs' size='340' side='right'caption='[[6jhs]], [[Resolution|resolution]] 3.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6jhs]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_hepatitis_a_virus_hu/australia/hm175/1976 Human hepatitis a virus hu/australia/hm175/1976] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JHS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JHS FirstGlance]. <br> | |||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6jhs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jhs OCA], [http://pdbe.org/6jhs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jhs RCSB], [http://www.ebi.ac.uk/pdbsum/6jhs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jhs ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 muM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development. | |||
Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.,Cao L, Liu P, Yang P, Gao Q, Li H, Sun Y, Zhu L, Lin J, Su D, Rao Z, Wang X PLoS Biol. 2019 Apr 30;17(4):e3000229. doi: 10.1371/journal.pbio.3000229., eCollection 2019 Apr. PMID:31039149<ref>PMID:31039149</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6jhs" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Human hepatitis a virus hu/australia/hm175/1976]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mus musculus]] | ||
[[Category: | [[Category: Cao, L]] | ||
[[Category: | [[Category: Gao, Q]] | ||
[[Category: | [[Category: Li, H]] | ||
[[Category: Lin, J]] | |||
[[Category: Liu, P]] | |||
[[Category: Rao, Z]] | |||
[[Category: Su, D]] | |||
[[Category: Sun, Y]] | |||
[[Category: Wang, X]] | |||
[[Category: Yang, P]] | |||
[[Category: Zhu, L]] | |||
[[Category: Complex]] | |||
[[Category: Hav]] | |||
[[Category: Icosahedral symmetry]] | |||
[[Category: Neutralizing antibody]] | |||
[[Category: Virus]] | |||
Latest revision as of 12:37, 18 March 2020
The cryo-EM structure of HAV bound to a neutralizing antibody-F7The cryo-EM structure of HAV bound to a neutralizing antibody-F7
Structural highlights
Publication Abstract from PubMedHepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 muM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development. Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.,Cao L, Liu P, Yang P, Gao Q, Li H, Sun Y, Zhu L, Lin J, Su D, Rao Z, Wang X PLoS Biol. 2019 Apr 30;17(4):e3000229. doi: 10.1371/journal.pbio.3000229., eCollection 2019 Apr. PMID:31039149[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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