7RL1 の概要
| エントリーDOI | 10.2210/pdb7rl1/pdb |
| EMDBエントリー | 24513 |
| 分子名称 | Capsid protein VP1, DNA (5'-D(*CP*A)-3') (2 entities in total) |
| 機能のキーワード | icosahedral capsid, aavrh.10, capsid engineering, adeno-associated virus, parvovirus, gene therapy, virus |
| 由来する生物種 | Adeno-associated virus 詳細 |
| タンパク質・核酸の鎖数 | 120 |
| 化学式量合計 | 3532847.40 |
| 構造登録者 | |
| 主引用文献 | Mietzsch, M.,Yu, J.C.,Hsi, J.,Chipman, P.,Broecker, F.,Fuming, Z.,Linhardt, R.J.,Seeberger, P.H.,Heilbronn, R.,McKenna, R.,Agbandje-McKenna, M. Structural Study of Aavrh.10 Receptor and Antibody Interactions. J.Virol., 95:e0124921-e0124921, 2021 Cited by PubMed Abstract: Recombinant adeno-associated virus (rAAV) vectors are one of the leading tools for the delivery of therapeutic genes in human gene therapy applications. For a successful transfer of their payload, the AAV vectors have to circumvent potential preexisting neutralizing host antibodies and bind to the receptors of the target cells. Both of these aspects have not been structurally analyzed for AAVrh.10. Here, cryo-electron microscopy and three-dimensional image reconstruction were used to map the binding site of sulfated -acetyllactosamine (LacNAc; previously shown to bind AAVrh.10) and a series of four monoclonal antibodies (MAbs). LacNAc was found to bind to a pocket located on the side of the 3-fold capsid protrusion that is mostly conserved to AAV9 and equivalent to its galactose-binding site. As a result, AAVrh.10 was also shown to be able to bind to cell surface glycans with terminal galactose. For the antigenic characterization, it was observed that several anti-AAV8 MAbs cross-react with AAVrh.10. The binding sites of these antibodies were mapped to the 3-fold capsid protrusions. Based on these observations, the AAVrh.10 capsid surface was engineered to create variant capsids that escape these antibodies while maintaining infectivity. Gene therapy vectors based on adeno-associated virus rhesus isolate 10 (AAVrh.10) have been used in several clinical trials to treat monogenetic diseases. However, compared to other AAV serotypes little is known about receptor binding and antigenicity of the AAVrh.10 capsid. Particularly, preexisting neutralizing antibodies against capsids are an important challenge that can hamper treatment efficiency. This study addresses both topics and identifies critical regions of the AAVrh.10 capsid for receptor and antibody binding. The insights gained were utilized to generate AAVrh.10 variants capable of evading known neutralizing antibodies. The findings of this study could further aid the utilization of AAVrh.10 vectors in clinical trials and help the approval of the subsequent biologics. PubMed: 34549984DOI: 10.1128/JVI.01249-21 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.71 Å) |
構造検証レポート
検証レポート(詳細版)
をダウンロード
をダウンロード
