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- EMDB-44319: Fab2-6 in complex with the capsid of Adeno-associated virus type 9 -

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Basic information

Entry
Database: EMDB / ID: EMD-44319
TitleFab2-6 in complex with the capsid of Adeno-associated virus type 9
Map data
Sample
  • Virus: Adeno-associated virus
    • Protein or peptide: Capsid protein VP1
  • Protein or peptide: Fab2-6 light chain
  • Protein or peptide: Fab2-6 heavy chain
KeywordsAdeno-associated virus / AAV / capsid / Fab-complex / antibody / NAb / VIRUS / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homologyPhospholipase 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 / T=1 icosahedral viral capsid / structural molecule activity / Capsid protein VP1
Function and homology information
Biological speciesAdeno-associated virus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsMietzsch M / McKenna R
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM082946 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural characterization of antibody-responses following Zolgensma treatment for AAV capsid engineering to expand patient cohorts.
Authors: Mario Mietzsch / Jane Hsi / Austin R Nelson / Neeta Khandekar / Ann-Maree Huang / Nicholas Jc Smith / Jon Zachary / Lindsay Potts / Michelle A Farrar / Paul Chipman / Mohammad Ghanem / Ian E ...Authors: Mario Mietzsch / Jane Hsi / Austin R Nelson / Neeta Khandekar / Ann-Maree Huang / Nicholas Jc Smith / Jon Zachary / Lindsay Potts / Michelle A Farrar / Paul Chipman / Mohammad Ghanem / Ian E Alexander / Grant J Logan / Juha T Huiskonen / Robert McKenna /
Abstract: Monoclonal antibodies are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids that are used as gene therapy delivery vectors. The presence of ...Monoclonal antibodies are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids that are used as gene therapy delivery vectors. The presence of pre-existing neutralizing antibodies in large portions of the human population poses a significant challenge for AAV-mediated gene therapy, primarily targeting the capsid leading to vector inactivation and loss of treatment efficacy. This study structurally characterizes the interactions of 21 human-derived neutralizing antibodies from three patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The antibodies bound to the 2-fold depression or the 3-fold protrusions do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with many antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with antibody escape phenotypes. These AAV9 capsid variants have the potential to expand the patient cohort to include those that were previously excluded due to their pre-existing neutralizing antibodies against the wtAAV9 capsid, and the possibly of further treatment to those requiring redosing.
History
DepositionMar 27, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44319.png

Downloads & links

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Map

FileDownload / File: emd_44319.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)X (Row.)Y (Col.)
0.83 Å/pix.
x 200 pix.
= 166.6 Å		0.83 Å/pix.
x 200 pix.
= 166.6 Å		0.83 Å/pix.
x 200 pix.
= 166.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.833 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-9.949816 - 17.729285999999998
Average (Standard dev.)0.000000004323886 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin-100-100-100
Dimensions200200200
Spacing200200200
CellA=B=C: 166.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_44319_half_map_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: #2

Fileemd_44319_half_map_2.map
Projections & Slices
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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
  • Protein or peptide: Fab2-6 light chain
  • Protein or peptide: Fab2-6 heavy chain

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Supramolecule #1: Adeno-associated virus

SupramoleculeName: Adeno-associated virus / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1 / NCBI-ID: 272636 / Sci species name: Adeno-associated virus / Virus type: VIRION / Virus isolate: SEROTYPE / Virus enveloped: No / Virus empty: No
Virus shellShell ID: 1 / T number (triangulation number): 1

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Macromolecule #1: Capsid protein VP1

MacromoleculeName: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Adeno-associated virus / Strain: AAV9
Molecular weightTheoretical: 59.873875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASGGGAPVA DNNEGADGVG SSSGNWHCDS QWLGDRVITT STRTWALPTY NNHLYKQISN STSGGSSNDN AYFGYSTPWG YFDFNRFHC HFSPRDWQRL INNNWGFRPK RLNFKLFNIQ VKEVTDNNGV KTIANNLTST VQVFTDSDYQ LPYVLGSAHE G CLPPFPAD ...String:
MASGGGAPVA DNNEGADGVG SSSGNWHCDS QWLGDRVITT STRTWALPTY NNHLYKQISN STSGGSSNDN AYFGYSTPWG YFDFNRFHC HFSPRDWQRL INNNWGFRPK RLNFKLFNIQ VKEVTDNNGV KTIANNLTST VQVFTDSDYQ LPYVLGSAHE G CLPPFPAD VFMIPQYGYL TLNDGSQAVG RSSFYCLEYF PSQMLRTGNN FQFSYEFENV PFHSSYAHSQ SLDRLMNPLI DQ YLYYLSK TINGSGQNQQ TLKFSVAGPS NMAVQGRNYI PGPSYRQQRV STTVTQNNNS EFAWPGASSW ALNGRNSLMN PGP AMASHK EGEDRFFPLS GSLIFGKQGT GRDNVDADKV MITNEEEIKT TNPVATESYG QVATNHQSAQ AQAQTGWVQN QGIL PGMVW QDRDVYLQGP IWAKIPHTDG NFHPSPLMGG FGMKHPPPQI LIKNTPVPAD PPTAFNKDKL NSFITQYSTG QVSVE IEWE LQKENSKRWN PEIQYTSNYY KSNNVEFAVN TEGVYSEPRP IGTRYLTRNL

UniProtKB: Capsid protein VP1

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Macromolecule #2: Fab2-6 light chain

MacromoleculeName: Fab2-6 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.170346 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EIVLTQSPGT LSLSPGERAT LSCRASQSVR SSYLAWYQQK PGQAPRLLIY GASSRATDIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGTSPAFG GGTKV

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Macromolecule #3: Fab2-6 heavy chain

MacromoleculeName: Fab2-6 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.821237 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLLESGGAL VQPGGSLRLS CAASGFSFSN YAMSWVRQAP GKGLEWVSTI SASGGTTYFA DSVKGHFTIS RDNSKNTLYL QMDSLRAED TAVYYCAKDP NYYDLSGYFL GGYYFDYWGQ GTLVTVSS

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2092947
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: PROJECTION MATCHING

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