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- PDB-6v10: genome-containing AAV8 particles -

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Basic information

Entry
Database: PDB / ID: 6v10
Titlegenome-containing AAV8 particles
Components
  • Capsid protein
  • DNA (5'-D(*CP*A)-3')
KeywordsVIRUS / AAV8 / capsid / genome / nucleotide binding pocket
Function / homology
Function and homology information


T=1 icosahedral viral capsid / nucleotide binding / structural molecule activity
Similarity search - Function
Phospholipase A2-like domain / Phospholipase A2-like domain / Parvovirus coat protein VP2 / Parvovirus coat protein VP1/VP2 / Parvovirus coat protein VP1/VP2 / Capsid/spike protein, ssDNA virus
Similarity search - Domain/homology
DNA / Capsid protein
Similarity search - Component
Biological speciesAdeno-associated virus - 8
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.77 Å
AuthorsMietzsch, M. / Agbandje-McKenna, M.
CitationJournal: J Virol / Year: 2020
Title: Comparative Analysis of the Capsid Structures of AAVrh.10, AAVrh.39, and AAV8.
Authors: Mario Mietzsch / Candace Barnes / Joshua A Hull / Paul Chipman / Jun Xie / Nilakshee Bhattacharya / Duncan Sousa / Robert McKenna / Guangping Gao / Mavis Agbandje-McKenna /
Abstract: Adeno-associated viruses (AAVs) from clade E are often used as vectors in gene delivery applications. This clade includes rhesus isolate 10 (AAVrh.10) and 39 (AAVrh.39) which, unlike representative ...Adeno-associated viruses (AAVs) from clade E are often used as vectors in gene delivery applications. This clade includes rhesus isolate 10 (AAVrh.10) and 39 (AAVrh.39) which, unlike representative AAV8, are capable of crossing the blood-brain barrier (BBB), thereby enabling the delivery of therapeutic genes to the central nervous system. Here, the capsid structures of AAV8, AAVrh.10 and AAVrh.39 have been determined by cryo-electron microscopy and three-dimensional image reconstruction to 3.08-, 2.75-, and 3.39-Å resolution, respectively, to enable a direct structural comparison. AAVrh.10 and AAVrh.39 are 98% identical in amino acid sequence but only ∼93.5% identical to AAV8. However, the capsid structures of all three viruses are similar, with only minor differences observed in the previously described surface variable regions, suggesting that specific residues S269 and N472, absent in AAV8, may confer the ability to cross the BBB in AAVrh.10 and AAVrh.39. Head-to-head comparison of empty and genome-containing particles showed DNA ordered in the previously described nucleotide-binding pocket, supporting the suggested role of this pocket in DNA packaging for the The structural characterization of these viruses provides a platform for future vector engineering efforts toward improved gene delivery success with respect to specific tissue targeting, transduction efficiency, antigenicity, or receptor retargeting. Recombinant adeno-associated virus vectors (rAAVs), based on AAV8 and AAVrh.10, have been utilized in multiple clinical trials to treat different monogenetic diseases. The closely related AAVrh.39 has also shown promise As recently attained for other AAV biologics, e.g., Luxturna and Zolgensma, based on AAV2 and AAV9, respectively, the vectors in this study will likely gain U.S. Food and Drug Administration approval for commercialization in the near future. This study characterized the capsid structures of these clinical vectors at atomic resolution using cryo-electron microscopy and image reconstruction for comparative analysis. The analysis suggested two key residues, S269 and N472, as determinants of BBB crossing for AAVrh.10 and AAVrh.39, a feature utilized for central nervous system delivery of therapeutic genes. The structure information thus provides a platform for engineering to improve receptor retargeting or tissue specificity. These are important challenges in the field that need attention. Capsid structure information also provides knowledge potentially applicable for regulatory product approval.
History
DepositionNov 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2019Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 11, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.0Jun 12, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_poly / entity_poly_seq / pdbx_entity_nonpoly / pdbx_entity_src_syn / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_ref / struct_ref_seq / struct_sheet / struct_sheet_order / struct_sheet_range / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_asym_id / _struct_site_gen.auth_seq_id / _struct_site_gen.label_asym_id / _struct_site_gen.label_seq_id
Revision 2.1Jun 4, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Capsid protein
B: Capsid protein
C: Capsid protein
D: Capsid protein
E: Capsid protein
F: Capsid protein
G: Capsid protein
H: Capsid protein
I: Capsid protein
J: Capsid protein
K: Capsid protein
L: Capsid protein
M: Capsid protein
N: Capsid protein
O: Capsid protein
P: Capsid protein
Q: Capsid protein
R: Capsid protein
S: Capsid protein
T: Capsid protein
U: Capsid protein
V: Capsid protein
W: Capsid protein
X: Capsid protein
Y: Capsid protein
Z: Capsid protein
a: Capsid protein
b: Capsid protein
c: Capsid protein
d: Capsid protein
e: Capsid protein
f: Capsid protein
g: Capsid protein
h: Capsid protein
i: Capsid protein
j: Capsid protein
k: Capsid protein
l: Capsid protein
m: Capsid protein
n: Capsid protein
o: Capsid protein
p: Capsid protein
q: Capsid protein
r: Capsid protein
s: Capsid protein
t: Capsid protein
u: Capsid protein
v: Capsid protein
w: Capsid protein
x: Capsid protein
y: Capsid protein
z: Capsid protein
1: Capsid protein
2: Capsid protein
3: Capsid protein
4: Capsid protein
5: Capsid protein
6: Capsid protein
7: Capsid protein
8: Capsid protein
0: DNA (5'-D(*CP*A)-3')
9: DNA (5'-D(*CP*A)-3')
AA: DNA (5'-D(*CP*A)-3')
BA: DNA (5'-D(*CP*A)-3')
CA: DNA (5'-D(*CP*A)-3')
DA: DNA (5'-D(*CP*A)-3')
EA: DNA (5'-D(*CP*A)-3')
FA: DNA (5'-D(*CP*A)-3')
GA: DNA (5'-D(*CP*A)-3')
HA: DNA (5'-D(*CP*A)-3')
IA: DNA (5'-D(*CP*A)-3')
JA: DNA (5'-D(*CP*A)-3')
KA: DNA (5'-D(*CP*A)-3')
LA: DNA (5'-D(*CP*A)-3')
MA: DNA (5'-D(*CP*A)-3')
NA: DNA (5'-D(*CP*A)-3')
OA: DNA (5'-D(*CP*A)-3')
PA: DNA (5'-D(*CP*A)-3')
QA: DNA (5'-D(*CP*A)-3')
RA: DNA (5'-D(*CP*A)-3')
SA: DNA (5'-D(*CP*A)-3')
TA: DNA (5'-D(*CP*A)-3')
UA: DNA (5'-D(*CP*A)-3')
VA: DNA (5'-D(*CP*A)-3')
WA: DNA (5'-D(*CP*A)-3')
XA: DNA (5'-D(*CP*A)-3')
YA: DNA (5'-D(*CP*A)-3')
ZA: DNA (5'-D(*CP*A)-3')
aA: DNA (5'-D(*CP*A)-3')
bA: DNA (5'-D(*CP*A)-3')
cA: DNA (5'-D(*CP*A)-3')
dA: DNA (5'-D(*CP*A)-3')
eA: DNA (5'-D(*CP*A)-3')
fA: DNA (5'-D(*CP*A)-3')
gA: DNA (5'-D(*CP*A)-3')
hA: DNA (5'-D(*CP*A)-3')
iA: DNA (5'-D(*CP*A)-3')
jA: DNA (5'-D(*CP*A)-3')
kA: DNA (5'-D(*CP*A)-3')
lA: DNA (5'-D(*CP*A)-3')
mA: DNA (5'-D(*CP*A)-3')
nA: DNA (5'-D(*CP*A)-3')
oA: DNA (5'-D(*CP*A)-3')
pA: DNA (5'-D(*CP*A)-3')
qA: DNA (5'-D(*CP*A)-3')
rA: DNA (5'-D(*CP*A)-3')
sA: DNA (5'-D(*CP*A)-3')
tA: DNA (5'-D(*CP*A)-3')
uA: DNA (5'-D(*CP*A)-3')
vA: DNA (5'-D(*CP*A)-3')
wA: DNA (5'-D(*CP*A)-3')
xA: DNA (5'-D(*CP*A)-3')
yA: DNA (5'-D(*CP*A)-3')
zA: DNA (5'-D(*CP*A)-3')
0A: DNA (5'-D(*CP*A)-3')
1A: DNA (5'-D(*CP*A)-3')
2A: DNA (5'-D(*CP*A)-3')
3A: DNA (5'-D(*CP*A)-3')
4A: DNA (5'-D(*CP*A)-3')
5A: DNA (5'-D(*CP*A)-3')


Theoretical massNumber of molelcules
Total (without water)3,552,837120
Polymers3,552,837120
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ...
Capsid protein


Mass: 58656.512 Da / Num. of mol.: 60
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Adeno-associated virus - 8 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8JQF8
#2: DNA chain ...
DNA (5'-D(*CP*A)-3')


Mass: 557.431 Da / Num. of mol.: 60 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Adeno-associated virus / Type: VIRUS / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Adeno-associated virus - 8 / Strain: AAV8
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Details of virusEmpty: NO / Enveloped: NO / Isolate: SEROTYPE / Type: VIRION
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 67 e/Å2 / Film or detector model: DIRECT ELECTRON DE-20 (5k x 3k)

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Processing

SoftwareName: PHENIX / Version: 1.10-2155_2155: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 3.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1072 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.009258540
ELECTRON MICROSCOPYf_angle_d0.784353160
ELECTRON MICROSCOPYf_dihedral_angle_d7.509203700
ELECTRON MICROSCOPYf_chiral_restr0.04636900
ELECTRON MICROSCOPYf_plane_restr0.00446620

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