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PDBsum entry 2qa0
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References listed in PDB file
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Key reference
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Title
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Structure of adeno-Associated virus serotype 8, A gene therapy vector.
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Authors
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H.J.Nam,
M.D.Lane,
E.Padron,
B.Gurda,
R.Mckenna,
E.Kohlbrenner,
G.Aslanidi,
B.Byrne,
N.Muzyczka,
S.Zolotukhin,
M.Agbandje-Mckenna.
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Ref.
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J Virol, 2007,
81,
12260-12271.
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PubMed id
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Abstract
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Adeno-associated viruses (AAVs) are being developed as gene therapy vectors, and
their efficacy could be improved by a detailed understanding of their viral
capsid structures. AAV serotype 8 (AAV8) shows a significantly greater liver
transduction efficiency than those of other serotypes, which has resulted in
efforts to develop this virus as a gene therapy vector for hemophilia A and
familial hypercholesterolemia. Pseudotyping studies show that the differential
tissue tropism and transduction efficiencies exhibited by the AAVs result from
differences in their capsid viral protein (VP) amino acids. Towards identifying
the structural features underpinning these disparities, we report the crystal
structure of the AAV8 viral capsid determined to 2.6-A resolution. The overall
topology of its common overlapping VP is similar to that previously reported for
the crystal structures of AAV2 and AAV4, with an eight-stranded beta-barrel and
long loops between the beta-strands. The most significant structural differences
between AAV8 and AAV2 (the best-characterized serotype) are located on the
capsid surface at protrusions surrounding the two-, three-, and fivefold axes at
residues reported to control transduction efficiency and antibody recognition
for AAV2. In addition, a comparison of the AAV8 and AAV2 capsid surface amino
acids showed a reduced distribution of basic charge for AAV8 at the mapped AAV2
heparin sulfate receptor binding region, consistent with an observed
non-heparin-binding phenotype for AAV8. Thus, this AAV8 structure provides an
additional platform for mutagenesis efforts to characterize AAV capsid regions
responsible for differential cellular tropism, transduction, and antigenicity
for these promising gene therapy vectors.
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