Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement...
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doaj-1268bed2dda34ef4a4cd0f369ef17e5f2021-01-16T00:02:57ZengMDPI AGViruses1999-49152021-01-011311111110.3390/v13010111Structure-Based Modeling of Complement C4 Mediated Neutralization of AdenovirusCorey C. Emerson0Phoebe L. Stewart1Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USAAdenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.https://www.mdpi.com/1999-4915/13/1/111adenovirusneutralizationneutralizing antibodycomplement C1complement C4molecular dynamics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Corey C. Emerson Phoebe L. Stewart |
spellingShingle |
Corey C. Emerson Phoebe L. Stewart Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus Viruses adenovirus neutralization neutralizing antibody complement C1 complement C4 molecular dynamics |
author_facet |
Corey C. Emerson Phoebe L. Stewart |
author_sort |
Corey C. Emerson |
title |
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus |
title_short |
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus |
title_full |
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus |
title_fullStr |
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus |
title_full_unstemmed |
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus |
title_sort |
structure-based modeling of complement c4 mediated neutralization of adenovirus |
publisher |
MDPI AG |
series |
Viruses |
issn |
1999-4915 |
publishDate |
2021-01-01 |
description |
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating. |
topic |
adenovirus neutralization neutralizing antibody complement C1 complement C4 molecular dynamics |
url |
https://www.mdpi.com/1999-4915/13/1/111 |
work_keys_str_mv |
AT coreycemerson structurebasedmodelingofcomplementc4mediatedneutralizationofadenovirus AT phoebelstewart structurebasedmodelingofcomplementc4mediatedneutralizationofadenovirus |
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1724336204962332672 |