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- EMDB-21049: Engineered oncolytic adenovirus Ad5-3M -

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Basic information

Entry
Database: EMDB / ID: EMD-21049
TitleEngineered oncolytic adenovirus Ad5-3M
Map data
Sample
  • Virus: Human adenovirus 5
Biological speciesHuman adenovirus 5
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsEmerson CC / Atasheva S / Shayakhmetov DM / Stewart PL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious DiseasesR01 AI107960 United States
CitationJournal: Sci Transl Med / Year: 2020
Title: Systemic cancer therapy with engineered adenovirus that evades innate immunity.
Authors: Svetlana Atasheva / Corey C Emerson / Jia Yao / Cedrick Young / Phoebe L Stewart / Dmitry M Shayakhmetov /
Abstract: Oncolytic virus therapy is a cancer treatment modality that has the potential to improve outcomes for patients with currently incurable malignancies. Although intravascular delivery of therapeutic ...Oncolytic virus therapy is a cancer treatment modality that has the potential to improve outcomes for patients with currently incurable malignancies. Although intravascular delivery of therapeutic viruses provides access to disseminated tumors, this delivery route exposes the virus to opsonizing and inactivating factors in the blood, which limit the effective therapeutic virus dose and contribute to activation of systemic toxicities. When human species C adenovirus HAdv-C5 is delivered intravenously, natural immunoglobulin M (IgM) antibodies and coagulation factor X rapidly opsonize HAdv-C5, leading to virus sequestration in tissue macrophages and promoting infection of liver cells, triggering hepatotoxicity. Here, we showed that natural IgM antibody binds to the hypervariable region 1 (HVR1) of the main HAdv-C5 capsid protein hexon. Using compound targeted mutagenesis of hexon HVR1 loop and other functional sites that mediate virus-host interactions, we engineered and obtained a high-resolution cryo-electron microscopy structure of an adenovirus vector, Ad5-3M, which resisted inactivation by blood factors, avoided sequestration in liver macrophages, and failed to trigger hepatotoxicity after intravenous delivery. Systemic delivery of Ad5-3M to mice with localized or disseminated lung cancer led to viral replication in tumor cells, suppression of tumor growth, and prolonged survival. Thus, compound targeted mutagenesis of functional sites in the virus capsid represents a generalizable approach to tailor virus interactions with the humoral and cellular arms of the immune system, enabling generation of "designer" viruses with improved therapeutic properties.
History
DepositionDec 2, 2019-
Header (metadata) releaseDec 11, 2019-
Map releaseNov 25, 2020-
UpdateDec 9, 2020-
Current statusDec 9, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21049.png

Downloads & links

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Map

FileDownload / File: emd_21049.map.gz / Format: CCP4 / Size: 600.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 2.08 Å
Density
Contour LevelBy AUTHOR: 1.1 / Movie #1: 1.1
Minimum - Maximum-9.405318 - 13.03463
Average (Standard dev.)0.03636626 (±1.1221563)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions540540540
Spacing540540540
CellA=B=C: 1123.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.082.082.08
M x/y/z540540540
origin x/y/z0.0000.0000.000
length x/y/z1123.2001123.2001123.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ240240240
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS540540540
D min/max/mean-9.40513.0350.036

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Supplemental data

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Sample components

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Entire : Human adenovirus 5

EntireName: Human adenovirus 5
Components
  • Virus: Human adenovirus 5

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Supramolecule #1: Human adenovirus 5

SupramoleculeName: Human adenovirus 5 / type: virus / ID: 1 / Parent: 0 / NCBI-ID: 28285 / Sci species name: Human adenovirus 5 / Sci species strain: HAdv-3M (three capsid mutations) / Virus type: VIRION / Virus isolate: OTHER / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Host systemOrganism: Homo sapiens (human)
Molecular weightTheoretical: 150 MDa
Virus shellShell ID: 1 / Name: capsid / Diameter: 900.0 Å / T number (triangulation number): 25

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 25.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2545
FSC plot (resolution estimation)

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