Atomic structure of a rationally engineered gene delivery vector, AAV2.5

被引：20

作者：

Burg, Matthew ^{[1
]}

Rosebrough, Claire ^{[1
]}

Drouin, Lauren M. ^{[1
,6
]}

Bennett, Antonette ^{[1
]}

Mietzsch, Mario ^{[1
]}

Chipman, Paul ^{[1
]}

McKenna, Robert ^{[1
]}

Sousa, Duncan ^{[2
]}

Potter, Mark ^{[3
,4
]}

Byrne, Barry ^{[3
,4
]}

Samulski, R. Jude ^{[5
]}

Agbandje-McKenna, Mavis ^{[1
]}

机构：

[1] Univ Florida, Coll Med, Dept Biochem & Mol Biol, McKnight Brain Inst, Gainesville, FL 32610 USA

[2] Florida State Univ, Dept Biol Sci, Biol Sci Imaging Resource, 89 Chieftan Way,Rm 119, Tallahassee, FL 32306 USA

[3] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA

[4] Univ Florida, Coll Med, Powell Gene Therapy Ctr, Gainesville, FL 32610 USA

[5] Univ N Carolina, Dept Pharmacol, Gene Therapy Ctr, Chapel Hill, NC 27515 USA

[6] Voyager Therapeut Inc, Cambridge, MA USA

来源：

JOURNAL OF STRUCTURAL BIOLOGY | 2018年 / 203卷 / 03期

关键词：

Adeno-associated virus; cryo-EM; Vector engineering; Structure-guided design; Parvovirus; THERAPY; TRANSDUCTION; INSIGHTS; BINDING; CELLS; MODEL;

D O I：

10.1016/j.jsb.2018.05.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

AAV2.5 represents the first structure-guided in-silica designed Adeno-associated virus (AAV) gene delivery vector. This engineered vector combined the receptor attachment properties of AAV serotype 2 (AAV2) with the muscle tropic properties of AAV1, and exhibited an antibody escape phenotype because of a modified antigenic epitope. To confirm the design, the structure of the vector was determined to a resolution of 2.78 angstrom using cryo-electron microscopy and image reconstruction. The structure of the major viral protein (VP), VP3, was ordered from residue 219 to 736, as reported for other AAV structures, and the five AAV2.5 residues exchanged from AAV2 to AAV1, Q263A, T265 (insertion), N706A, V709A, and T717N, were readily interpretable. Significantly, the surface loops containing these residues adopt the AAV1 conformation indicating the importance of amino acid residues in dictating VP structure.

引用

页码：236 / 241

页数：6