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-Structure paper
タイトル | Structural characterization of a bat Adeno-associated virus capsid. |
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ジャーナル・号・ページ | J Struct Biol, Vol. 211, Issue 2, Page 107547, Year 2020 |
掲載日 | 2020年8月1日 |
著者 | Mario Mietzsch / Ya Li / Justin Kurian / James Kennon Smith / Paul Chipman / Robert McKenna / Lin Yang / Mavis Agbandje-McKenna / |
PubMed 要旨 | Adeno-associated viruses (AAVs) are widespread among vertebrates. AAVs isolated from bats display low capsid protein sequence identities (<60%) to AAV2, AAV5, and other primate AAVs. Here we report the first capsid structure of a non-primate AAV which was isolated from bats. The capsid structure of BtAAV-10HB (10HB) was determined by cryo-electron microscopy and three-dimensional image reconstruction to 3.03 Å resolution. Comparison of empty and genome-containing capsids showed that the capsid structures are almost identical except for an ordered nucleotide in a previously described nucleotide-binding pocket, the density in the 5-fold channel, and several amino acids with altered side chain conformations. Compared to other dependoparvoviruses, for example AAV2 and AAV5, 10HB displays unique structural features including insertions and deletions in capsid surface loops. Overall, the 10HB capsid structure superposes with an RMSD of 1.7 Å and 1.8 Å to AAV2 and AAV5, respectively. Currently all approved AAV human gene therapy biologics and vectors in clinical trials are based on primate isolates. However, pre-existing neutralizing antibodies in the human population represents a hurdle to their use. 10HB capsids are capable of packaging AAV2 vector genomes and thus have potential as gene delivery vectors. Significantly, a screen with human sera showed lack of recognition by the 10HB capsid. Thus, the different capsid surface of 10HB vectors likely renders it "invisible" to potential pre-existing neutralizing human anti-AAV antibodies especially because this virus or similar variants do not exist in primate populations. |
リンク | J Struct Biol / PubMed:32522552 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.03 Å |
構造データ | EMDB-21656, PDB-6wft: EMDB-21657, PDB-6wfu: |
化合物 | ChemComp-D5M: |
由来 |
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キーワード | VIRUS / Icosahedral Capsid / AAV / Gene Therapy / non-primate / Bat |