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- PDB-9p4l: Cryo-EM structure of AAV.CAP-B10 -

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Basic information

Entry
Database: PDB / ID: 9p4l
TitleCryo-EM structure of AAV.CAP-B10
ComponentsCapsid protein VP1
KeywordsVIRUS / AAV / liver / detarget / PHP.eB / CAP-B10
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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.22 Å
AuthorsBrittain, T.J. / Jang, S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)DP1NS111369 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)UF1MH128336 United States
CitationJournal: Mol Ther / Year: 2026
Title: Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids.
Authors: Tyler J Brittain / Seongmin Jang / Gerard M Coughlin / Jonathan D Hoang / Bre'Anna H Barcelona / Izabela Giriat / Fiona Ristic / Nathan Appling / Camille P M A Chossis / Timothy F Shay / Viviana Gradinaru /
Abstract: Developing effective vectors for gene therapy requires accurate on-target coverage while minimizing off-target transduction that can lead to adverse events. In mice, the engineered capsid PHP.eB ...Developing effective vectors for gene therapy requires accurate on-target coverage while minimizing off-target transduction that can lead to adverse events. In mice, the engineered capsid PHP.eB shows enhanced brain transduction, while the further engineered CAP-B10 is also de-targeted from astrocytes and liver. Here, we solved cryoelectron microscopy (cryo-EM) structures of CAP-B10 and its complex with the adeno-associated virus receptor (AAVR) domain PKD2, at 2.22- and 2.20-Å resolutions, respectively. These structures reveal a motif that hinders AAVR binding, which we confirmed by measuring affinities. We showed that this motif is transferable to other capsids by solving cryo-EM structures of AAV9-X1, at 3.09 Å, and AAV9-X1.1 without and with PKD2, at 2.51 and 2.18 Å, respectively. Using this structural information, we designed and validated novel AAV variants with reduced liver and altered brain cell tropism in vivo. Overall, we provide a framework for using structural information to guide rational engineering of gene delivery vectors to achieve safe and effective delivery.
History
DepositionJun 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Apr 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 20, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1May 20, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Capsid protein VP1


Theoretical massNumber of molelcules
Total (without water)82,1621
Polymers82,1621
Non-polymers00
Water00
1
A: Capsid protein VP1
x 60


Theoretical massNumber of molelcules
Total (without water)4,929,69960
Polymers4,929,69960
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59

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Components

#1: Protein Capsid protein VP1


Mass: 82161.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CAP-B10 VP1 / Source: (gene. exp.) Adeno-associated virus / Gene: cap / Production host: Homo sapiens (human) / References: UniProt: Q6JC22
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: all / Source: RECOMBINANT
Source (natural)Organism: Adeno-associated virus
Source (recombinant)Organism: Homo sapiens (human)
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 4000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104127 / Symmetry type: POINT
RefinementHighest resolution: 2.22 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034287
ELECTRON MICROSCOPYf_angle_d0.4665840
ELECTRON MICROSCOPYf_dihedral_angle_d4.307567
ELECTRON MICROSCOPYf_chiral_restr0.043599
ELECTRON MICROSCOPYf_plane_restr0.004776

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