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PDBsum entry 2qa0
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* Residue conservation analysis
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J Virol
81:12260-12271
(2007)
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PubMed id:
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Structure of adeno-associated virus serotype 8, a gene therapy vector.
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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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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.Wang,
S.M.Faust,
and
J.E.Rabinowitz
(2011).
The next step in gene delivery: molecular engineering of adeno-associated virus serotypes.
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J Mol Cell Cardiol,
50,
793-802.
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A.Asokan,
J.C.Conway,
J.L.Phillips,
C.Li,
J.Hegge,
R.Sinnott,
S.Yadav,
N.DiPrimio,
H.J.Nam,
M.Agbandje-McKenna,
S.McPhee,
J.Wolff,
and
R.J.Samulski
(2010).
Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle.
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Nat Biotechnol,
28,
79-82.
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A.Asokan
(2010).
Reengineered AAV vectors: old dog, new tricks.
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Discov Med,
9,
399-403.
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C.C.Chen,
C.P.Sun,
H.I.Ma,
C.C.Fang,
P.Y.Wu,
X.Xiao,
and
M.H.Tao
(2009).
Comparative study of anti-hepatitis B virus RNA interference by double-stranded adeno-associated virus serotypes 7, 8, and 9.
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Mol Ther,
17,
352-359.
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F.P.Manfredsson,
A.C.Rising,
and
R.J.Mandel
(2009).
AAV9: a potential blood-brain barrier buster.
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Mol Ther,
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403-405.
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J.T.Koerber,
R.Klimczak,
J.H.Jang,
D.Dalkara,
J.G.Flannery,
and
D.V.Schaffer
(2009).
Molecular evolution of adeno-associated virus for enhanced glial gene delivery.
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Mol Ther,
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2088-2095.
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K.J.Excoffon,
J.T.Koerber,
D.D.Dickey,
M.Murtha,
S.Keshavjee,
B.K.Kaspar,
J.Zabner,
and
D.V.Schaffer
(2009).
Directed evolution of adeno-associated virus to an infectious respiratory virus.
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Proc Natl Acad Sci U S A,
106,
3865-3870.
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L.H.Vandenberghe,
E.Breous,
H.J.Nam,
G.Gao,
R.Xiao,
A.Sandhu,
J.Johnston,
Z.Debyser,
M.Agbandje-McKenna,
and
J.M.Wilson
(2009).
Naturally occurring singleton residues in AAV capsid impact vector performance and illustrate structural constraints.
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Gene Ther,
16,
1416-1428.
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L.H.Vandenberghe,
J.M.Wilson,
and
G.Gao
(2009).
Tailoring the AAV vector capsid for gene therapy.
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Gene Ther,
16,
311-319.
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L.Yang,
J.Jiang,
L.M.Drouin,
M.Agbandje-McKenna,
C.Chen,
C.Qiao,
D.Pu,
X.Hu,
D.Z.Wang,
J.Li,
and
X.Xiao
(2009).
A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection.
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Proc Natl Acad Sci U S A,
106,
3946-3951.
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M.A.Kennedy,
and
R.J.Parks
(2009).
Adenovirus virion stability and the viral genome: size matters.
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Mol Ther,
17,
1664-1666.
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M.Mitchell,
H.J.Nam,
A.Carter,
A.McCall,
C.Rence,
A.Bennett,
B.Gurda,
R.McKenna,
M.Porter,
Y.Sakai,
B.J.Byrne,
N.Muzyczka,
G.Aslanidi,
S.Zolotukhin,
and
M.Agbandje-McKenna
(2009).
Production, purification and preliminary X-ray crystallographic studies of adeno-associated virus serotype 9.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
65,
715-718.
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S.Youjin,
and
Y.Jun
(2009).
The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy.
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Biotechnol Lett,
31,
321-328.
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T.F.Lerch,
Q.Xie,
H.M.Ongley,
J.Hare,
and
M.S.Chapman
(2009).
Twinned crystals of adeno-associated virus serotype 3b prove suitable for structural studies.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
65,
177-183.
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T.K.Park,
Z.Wu,
S.Kjellstrom,
Y.Zeng,
R.A.Bush,
P.A.Sieving,
and
P.Colosi
(2009).
Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse.
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Gene Ther,
16,
916-926.
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B.R.Schultz,
and
J.S.Chamberlain
(2008).
Recombinant adeno-associated virus transduction and integration.
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Mol Ther,
16,
1189-1199.
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D.V.Schaffer,
J.T.Koerber,
and
K.I.Lim
(2008).
Molecular engineering of viral gene delivery vehicles.
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Annu Rev Biomed Eng,
10,
169-194.
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J.T.Koerber,
J.H.Jang,
and
D.V.Schaffer
(2008).
DNA shuffling of adeno-associated virus yields functionally diverse viral progeny.
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Mol Ther,
16,
1703-1709.
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N.DiPrimio,
A.Asokan,
L.Govindasamy,
M.Agbandje-McKenna,
and
R.J.Samulski
(2008).
Surface loop dynamics in adeno-associated virus capsid assembly.
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J Virol,
82,
5178-5189.
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Q.Xie,
H.M.Ongley,
J.Hare,
and
M.S.Chapman
(2008).
Crystallization and preliminary X-ray structural studies of adeno-associated virus serotype 6.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
64,
1074-1078.
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S.G.Beattie,
E.Goetzman,
T.Conlon,
S.Germain,
G.Walter,
M.Campbell-Thompson,
D.Matern,
J.Vockley,
and
T.R.Flotte
(2008).
Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD.
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Hum Gene Ther,
19,
579-588.
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S.L.Murphy,
A.Bhagwat,
S.Edmonson,
S.Zhou,
and
K.A.High
(2008).
High-throughput screening and biophysical interrogation of hepatotropic AAV.
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Mol Ther,
16,
1960-1967.
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W.Li,
A.Asokan,
Z.Wu,
T.Van Dyke,
N.DiPrimio,
J.S.Johnson,
L.Govindaswamy,
M.Agbandje-McKenna,
S.Leichtle,
D.E.Redmond,
T.J.McCown,
K.B.Petermann,
N.E.Sharpless,
and
R.J.Samulski
(2008).
Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles.
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Mol Ther,
16,
1252-1260.
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O.Quesada,
B.Gurda,
L.Govindasamy,
R.McKenna,
E.Kohlbrenner,
G.Aslanidi,
S.Zolotukhin,
N.Muzyczka,
and
M.Agbandje-McKenna
(2007).
Production, purification and preliminary X-ray crystallographic studies of adeno-associated virus serotype 7.
|
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
63,
1073-1076.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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