6cbe | pdb_00006cbe
Atomic structure of a rationally engineered gene delivery vector, AAV2.5
Structural highlights
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Function[CAPSD_AAV2S] Capsid protein self-assembles to form an icosahedral capsid with a T=1 symmetry, about 22 nm in diameter, and consisting of 60 copies of three size variants of the capsid protein VP1, VP2 and VP3 which differ in their N-terminus. The capsid encapsulates the genomic ssDNA. Binds to host cell heparan sulfate and uses host ITGA5-ITGB1 as coreceptor on the cell surface to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin-dependent endocytosis. Binding to the host receptor also induces capsid rearrangements leading to surface exposure of VP1 N-terminus, specifically its phospholipase A2-like region and putative nuclear localization signal(s). VP1 N-terminus might serve as a lipolytic enzyme to breach the endosomal membrane during entry into host cell and might contribute to virus transport to the nucleus.[1] [2] [3] [4] Publication Abstract from PubMedAAV2.5 represents the first structure-guided in-silico 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 2.78A 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. Atomic structure of a rationally engineered gene delivery vector, AAV2.5.,Burg M, Rosebrough C, Drouin LM, Bennett A, Mietzsch M, Chipman P, McKenna R, Sousa D, Potter M, Byrne B, Jude Samulski R, Agbandje-McKenna M J Struct Biol. 2018 May 18. pii: S1047-8477(18)30119-9. doi:, 10.1016/j.jsb.2018.05.004. PMID:29775653[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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