Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus.
Viruses
; 13(1)2021 Jan 15.
Article
in English
| MEDLINE | ID: covidwho-1038679
ABSTRACT
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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Complement C4
/
Models, Molecular
/
Adenoviridae
Limits:
Humans
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
V13010111
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