Type-Specific Epitope Locations Revealed by X-Ray Crystallographic Study of Adenovirus Type 5 Hexon

A major obstacle to the use of adenovirus as a vector for gene therapy is the host immune response to hexon, the major protein component of the icosahedral capsid. A solution lies in creating novel vectors with modified or chimeric hexons to evade the immune response to native hexon. The crystal str...

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Bibliographic Details
Published in:Molecular therapy 2000-01, Vol.1 (1), p.18-30
Main Authors: Rux, John J., Burnett, Roger M.
Format: Article
Language:English
Subjects:
adenovirus
Adenoviruses
Adenoviruses, Human - chemistry
Adenoviruses, Human - genetics
Adenoviruses, Human - immunology
Antigens, Viral - chemistry
Antigens, Viral - genetics
Capsid - chemistry
Capsid - genetics
Capsid - immunology
Capsid Proteins
Crystallography
Crystallography, X-Ray
Drug Design
epitopes
Epitopes - chemistry
Epitopes - genetics
Gene therapy
Genetic Therapy
Genetic Vectors
Genomes
hexon
Humans
Models, Molecular
Protein Conformation
Protein Engineering
Protein Structure, Quaternary
Proteins
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
Vectors (Biology)
X-ray diffraction
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Summary:A major obstacle to the use of adenovirus as a vector for gene therapy is the host immune response to hexon, the major protein component of the icosahedral capsid. A solution lies in creating novel vectors with modified or chimeric hexons to evade the immune response to native hexon. The crystal structure of hexon from human adenovirus type 5 (ad5), the type primarily used for gene therapy, has been determined to facilitate the design of such molecules. As the 951-amino-acid (aa) ad5 hexon sequence is closely related to that of ad2 (967 aa; 86% aa identity), the ad5 structure was solved by molecular replacement with a model constructed from the known ad2 hexon. During refinement, greater than 25% of the sequence was reassigned, resulting in a relocation of two epitope regions, from buried positions in the ad2 model to external sites at the top of the ad5 molecule. The resultant model is in better agreement with crystallographic data, while maintaining the overall topology of ad2 hexon. This work suggests that all hexons have the same basic fold and that the ad5 hexon structure provides an accurate and representative model for designing new adenovirus vectors.
ISSN:1525-0016
1525-0024
DOI:10.1006/mthe.1999.0001