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- EMDB-20630: The atomic structure of a human adeno-associated virus capsid iso... -

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Basic information

Entry
Database: EMDB / ID: EMD-20630
TitleThe atomic structure of a human adeno-associated virus capsid isolate (AAVhu69/AAVv66)
Map dataadeno-associated virus capsid isolate (AAVhu69/AAVv66)
Sample
  • Virus: Adeno-associated virus
    • Protein or peptide: Capsid protein VP1
Keywordsadeno-associated virus / AAV / VIRUS
Function / homologyPhospholipase A2-like domain / Phospholipase A2-like domain / Parvovirus coat protein VP2 / Parvovirus coat protein VP1/VP2 / Parvovirus coat protein VP2 / Capsid/spike protein, ssDNA virus / T=1 icosahedral viral capsid / structural molecule activity / Capsid protein VP1
Function and homology information
Biological speciesAdeno-associated virus
Methodsingle particle reconstruction / Resolution: 2.46 Å
AuthorsHsu H-L / Brown A
Funding support United States, 7 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)2R01NS076991 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)5P01HL131471 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)5P01HD080642 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)5R01AI121135 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)UG3HL147367 United States
Department of Defense (DOD, United States)W81XWH-17-1-0212 United States
Bill & Melinda Gates FoundationOPP1132169 United States
CitationJournal: Nat Commun / Year: 2020
Title: Structural characterization of a novel human adeno-associated virus capsid with neurotropic properties.
Authors: Hung-Lun Hsu / Alexander Brown / Anna B Loveland / Anoushka Lotun / Meiyu Xu / Li Luo / Guangchao Xu / Jia Li / Lingzhi Ren / Qin Su / Dominic J Gessler / Yuquan Wei / Phillip W L Tai / ...Authors: Hung-Lun Hsu / Alexander Brown / Anna B Loveland / Anoushka Lotun / Meiyu Xu / Li Luo / Guangchao Xu / Jia Li / Lingzhi Ren / Qin Su / Dominic J Gessler / Yuquan Wei / Phillip W L Tai / Andrei A Korostelev / Guangping Gao /
Abstract: Recombinant adeno-associated viruses (rAAVs) are currently considered the safest and most reliable gene delivery vehicles for human gene therapy. Three serotype capsids, AAV1, AAV2, and AAV9, have ...Recombinant adeno-associated viruses (rAAVs) are currently considered the safest and most reliable gene delivery vehicles for human gene therapy. Three serotype capsids, AAV1, AAV2, and AAV9, have been approved for commercial use in patients, but they may not be suitable for all therapeutic contexts. Here, we describe a novel capsid identified in a human clinical sample by high-throughput, long-read sequencing. The capsid, which we have named AAVv66, shares high sequence similarity with AAV2. We demonstrate that compared to AAV2, AAVv66 exhibits enhanced production yields, virion stability, and CNS transduction. Unique structural properties of AAVv66 visualized by cryo-EM at 2.5-Å resolution, suggest that critical residues at the three-fold protrusion and at the interface of the five-fold axis of symmetry likely contribute to the beneficial characteristics of AAVv66. Our findings underscore the potential of AAVv66 as a gene therapy vector.
History
DepositionAug 22, 2019-
Header (metadata) releaseOct 2, 2019-
Map releaseMay 27, 2020-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.6
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3.6
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6u3q
  • Surface level: 6
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6u3q
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20630.png

Downloads & links

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Map

FileDownload / File: emd_20630.map.gz / Format: CCP4 / Size: 729 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationadeno-associated virus capsid isolate (AAVhu69/AAVv66)
Voxel sizeX=Y=Z: 1.059 Å
Density
Contour LevelBy AUTHOR: 3.6 / Movie #1: 3.6
Minimum - Maximum-7.268458 - 22.946484000000002
Average (Standard dev.)0.000000000003371 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions576576576
Spacing576576576
CellA=B=C: 609.984 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0591.0591.059
M x/y/z576576576
origin x/y/z0.0000.0000.000
length x/y/z609.984609.984609.984
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS576576576
D min/max/mean-7.26822.9460.000

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Supplemental data

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Sample components

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Entire : Adeno-associated virus

EntireName: Adeno-associated virus
Components
  • Virus: Adeno-associated virus
    • Protein or peptide: Capsid protein VP1

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Supramolecule #1: Adeno-associated virus

SupramoleculeName: Adeno-associated virus / type: virus / ID: 1 / Parent: 0 / Macromolecule list: all / NCBI-ID: 272636 / Sci species name: Adeno-associated virus / Virus type: VIRION / Virus isolate: SEROTYPE / Virus enveloped: No / Virus empty: No

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Macromolecule #1: Capsid protein VP1

MacromoleculeName: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 60 / Enantiomer: LEVO
Source (natural)Organism: Adeno-associated virus
Molecular weightTheoretical: 81.823031 KDa
SequenceString: MAADGYLPDW LEDTLSEGIR QWWKLKPGPP PPKPAERHQD DSRGLVLPGY KYLGPFNGLD KGEPVNEADA AALEHDKAYD RQLDSGDNP YLKYNHADAE FQERLKEDTS FGGNLGRAVF QAKKRVLEPL GLVEEPVKTA PGKKRPVEHS PAEPDSSSGT G KAGQQPAR ...String:
MAADGYLPDW LEDTLSEGIR QWWKLKPGPP PPKPAERHQD DSRGLVLPGY KYLGPFNGLD KGEPVNEADA AALEHDKAYD RQLDSGDNP YLKYNHADAE FQERLKEDTS FGGNLGRAVF QAKKRVLEPL GLVEEPVKTA PGKKRPVEHS PAEPDSSSGT G KAGQQPAR KRLNFGQTGD ADSVPDPQPL GQPPAAPSGL GTNTMATGSG APMADNNEGA DGVGNSSGNW HCDSTWMGDR VI TTSTRTW ALPTYNNHLY KQISSQSGAS NDNHYFGYST PWGYFDFNRF HCHFSPRDWQ RLINNNWGFR PKRLNFKLFN IQV KEVTQN DGTTTIANNL TSTVQVFTDS EYQLPYVLGS AHQGCLPPFP ADVFMVPQYG YLTLNNGSQA VGRSSFYCLE YFPS QMLRT GNNFTFSYTF EDVPFHSSYA HSQSLDRLMN PLIDQYLYYL SKTNAPSGTT TMSRLQFSQA GASDIRDQSR NWLPG PCYR QQRVSKTAAD NNNSDYSWTG ATKYHLNGRD SLVNPGPAMA SHKDDEEKYF PQSGVLIFGK QDSGKTNVDI EKVMIT DEE EIRTTNPVAT EQYGSVSTNL QSGNTQAATT DVNTQGVLPG MVWQDRDVYL QGPIWAKIPH TDGHFHPSPL MGGFGLK HP PPQILIKNTP VPANPSTTFS AAKFASFITQ YSTGQVSVEI EWELQKENSK RWNPEIQYTS NYNKSVNVDF TVDTNGVY S EPRPIGTRYL TRNL

UniProtKB: Capsid protein VP1

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Experimental details

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Structure determination

Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
Component:
ConcentrationFormulaName
8.0 g/LNaClsodium chloride
0.2 g/LKClpotassium chloride
1.44 g/LNa2HPO4Disodium phosphate
0.24 g/LKH2PO4Monopotassium phosphate
50.0 g/LC6H14O6D-sorbital
0.001 %pluronic acid F68

Details: filtered through 0.22 um filter
GridMaterial: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Support film - Film thickness: 3 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 48.62 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 52874
Startup modelType of model: OTHER / Details: ab-initio 3D
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52874
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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