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- PDB-9p4n: Cryo-EM structure of AAV9-X1.1 complexed to AAVR-PKD2 -

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Basic information

Entry
Database: PDB / ID: 9p4n
TitleCryo-EM structure of AAV9-X1.1 complexed to AAVR-PKD2
Components
  • Capsid protein VP1
  • Dyslexia-associated protein KIAA0319-like protein
KeywordsVIRUS / AAV / liver / detarget / AAV9-X1.1 / X1.1 / LRP6 / AAVR / PKD2
Function / homology
Function and homology information


proacrosomal vesicle fusion / acrosome assembly / response to auditory stimulus / flagellated sperm motility / T=1 icosahedral viral capsid / receptor-mediated endocytosis of virus by host cell / trans-Golgi network / neuron migration / cytoplasmic vesicle / spermatogenesis ...proacrosomal vesicle fusion / acrosome assembly / response to auditory stimulus / flagellated sperm motility / T=1 icosahedral viral capsid / receptor-mediated endocytosis of virus by host cell / trans-Golgi network / neuron migration / cytoplasmic vesicle / spermatogenesis / Golgi membrane / nucleolus / structural molecule activity / Golgi apparatus / membrane / plasma membrane
Similarity search - Function
Dyslexia-associated protein KIAA0319-like / : / Dyslexia-associated protein KIAA0319 N-terminal domain / KIAA0319 C-terminal domain / MANSC domain / MANSC domain profile. / K319L-like, PKD domain / Polycystic kidney disease (PKD) domain profile. / PKD domain / PKD domain superfamily ...Dyslexia-associated protein KIAA0319-like / : / Dyslexia-associated protein KIAA0319 N-terminal domain / KIAA0319 C-terminal domain / MANSC domain / MANSC domain profile. / K319L-like, PKD domain / Polycystic kidney disease (PKD) domain profile. / PKD domain / PKD domain superfamily / PKD/Chitinase domain / Repeats in polycystic kidney disease 1 (PKD1) and other proteins / 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 / Immunoglobulin-like fold
Similarity search - Domain/homology
Capsid protein VP1 / Dyslexia-associated protein KIAA0319-like protein
Similarity search - Component
Biological speciesAdeno-associated virus
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.18 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Capsid protein VP1
R: Dyslexia-associated protein KIAA0319-like protein


Theoretical massNumber of molelcules
Total (without water)95,7482
Polymers95,7482
Non-polymers00
Water00
1
A: Capsid protein VP1
R: Dyslexia-associated protein KIAA0319-like protein
x 60


Theoretical massNumber of molelcules
Total (without water)5,744,909120
Polymers5,744,909120
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59

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Components

#1: Protein Capsid protein VP1


Mass: 82160.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: AAV9-X1.1 VP1 / Source: (gene. exp.) Adeno-associated virus / Gene: cap / Production host: Homo sapiens (human) / References: UniProt: Q6JC22
#2: Protein Dyslexia-associated protein KIAA0319-like protein / Adeno-associated virus receptor / AAVR


Mass: 13587.939 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Kiaa0319l, Aavr / Production host: Escherichia coli (E. coli) / References: UniProt: Q8K135
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: 2.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 81365 / Symmetry type: POINT
RefinementHighest resolution: 2.18 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0025021
ELECTRON MICROSCOPYf_angle_d0.4586843
ELECTRON MICROSCOPYf_dihedral_angle_d3.829666
ELECTRON MICROSCOPYf_chiral_restr0.042723
ELECTRON MICROSCOPYf_plane_restr0.003907

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