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- PDB-5ogi: Complex of a binding protein and human adenovirus C 5 hexon -

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Basic information

Entry
Database: PDB / ID: 5ogi
TitleComplex of a binding protein and human adenovirus C 5 hexon
Components
  • Hexon protein
  • scFv of 9C12 antibody
KeywordsVIRAL PROTEIN / Antibody / Human Adenovirus C5 / gene therapy
Function / homology
Function and homology information


T=25 icosahedral viral capsid / microtubule-dependent intracellular transport of viral material towards nucleus / host cell / viral capsid / symbiont entry into host cell / host cell nucleus / structural molecule activity
Similarity search - Function
Adenovirus Pll, hexon, subdomain 2 / Adenovirus hexon protein / Adenovirus Pll, hexon, N-terminal / Adenovirus Pll, hexon, C-terminal / Hexon, adenovirus major coat protein, N-terminal domain / Hexon, adenovirus major coat protein, C-terminal domain / Group II dsDNA virus coat/capsid protein
Similarity search - Domain/homology
1,4-DIETHYLENE DIOXIDE / Hexon protein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Human adenovirus C serotype 5
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSchmid, M. / Ernst, P. / Honegger, A. / Suomalainen, M. / Zimmermann, M. / Braun, L. / Stauffer, S. / Thom, C. / Dreier, B. / Eibauer, M. ...Schmid, M. / Ernst, P. / Honegger, A. / Suomalainen, M. / Zimmermann, M. / Braun, L. / Stauffer, S. / Thom, C. / Dreier, B. / Eibauer, M. / Kipar, A. / Vogel, V. / Greber, U.F. / Medalia, O. / Plueckthun, A.
CitationJournal: Nat Commun / Year: 2018
Title: Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.
Authors: Markus Schmid / Patrick Ernst / Annemarie Honegger / Maarit Suomalainen / Martina Zimmermann / Lukas Braun / Sarah Stauffer / Cristian Thom / Birgit Dreier / Matthias Eibauer / Anja Kipar / ...Authors: Markus Schmid / Patrick Ernst / Annemarie Honegger / Maarit Suomalainen / Martina Zimmermann / Lukas Braun / Sarah Stauffer / Cristian Thom / Birgit Dreier / Matthias Eibauer / Anja Kipar / Viola Vogel / Urs F Greber / Ohad Medalia / Andreas Plückthun /
Abstract: Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we ...Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hexon symmetry and gain avidity. The shield reduces virion clearance in the liver. When the shielded particles are equipped with adaptor proteins, the virions deliver their payload genes into human cancer cells expressing HER2 or EGFR. The combination of shield and adapter also increases viral gene delivery to xenografted tumors in vivo, reduces liver off-targeting and immune neutralization. Our study highlights the power of protein engineering for viral vectors overcoming the challenges of local and systemic viral gene therapies.
History
DepositionJul 13, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hexon protein
B: scFv of 9C12 antibody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,69524
Polymers135,2992
Non-polymers2,39722
Water4,774265
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5410 Å2
ΔGint-21 kcal/mol
Surface area58900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.185, 158.185, 140.805
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

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Protein / Antibody , 2 types, 2 molecules AB

#1: Protein Hexon protein / CP-H / Protein II


Mass: 108042.469 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human adenovirus C serotype 5 / References: UniProt: P04133
#2: Antibody scFv of 9C12 antibody


Mass: 27256.225 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 5 types, 287 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C4H8O2
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.76 Å3/Da / Density % sol: 67.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 1.6 M (NH4)2SO4, 10 % dioxane, 0.1 M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→49.09 Å / Num. obs: 49257 / % possible obs: 100 % / Redundancy: 21.1 % / Rrim(I) all: 0.427 / Net I/σ(I): 9.76
Reflection shellResolution: 2.8→2.87 Å / Rrim(I) all: 5.467

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TG7

3tg7


Resolution: 2.8→49.09 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.82
RfactorNum. reflection% reflectionSelection details
Rfree0.2346 2462 5 %RANDOM
Rwork0.1983 ---
obs0.2001 49250 99.96 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.8→49.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9176 0 147 265 9588
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029598
X-RAY DIFFRACTIONf_angle_d0.57113023
X-RAY DIFFRACTIONf_dihedral_angle_d12.4355697
X-RAY DIFFRACTIONf_chiral_restr0.0431358
X-RAY DIFFRACTIONf_plane_restr0.0031689
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.85380.42571360.38782588X-RAY DIFFRACTION100
2.8538-2.91210.33451370.35292608X-RAY DIFFRACTION100
2.9121-2.97540.34351350.31962559X-RAY DIFFRACTION100
2.9754-3.04460.40241380.29742625X-RAY DIFFRACTION100
3.0446-3.12070.29571350.27282555X-RAY DIFFRACTION100
3.1207-3.20510.29981360.26672599X-RAY DIFFRACTION100
3.2051-3.29940.28571380.25292605X-RAY DIFFRACTION100
3.2994-3.40590.27711350.2432571X-RAY DIFFRACTION100
3.4059-3.52760.27291370.22642605X-RAY DIFFRACTION100
3.5276-3.66880.24921370.20012595X-RAY DIFFRACTION100
3.6688-3.83570.21251360.18482592X-RAY DIFFRACTION100
3.8357-4.03780.20741360.17092586X-RAY DIFFRACTION100
4.0378-4.29060.15991370.15252598X-RAY DIFFRACTION100
4.2906-4.62170.19031370.14272605X-RAY DIFFRACTION100
4.6217-5.08640.18921370.14512605X-RAY DIFFRACTION100
5.0864-5.82140.20721370.16062608X-RAY DIFFRACTION100
5.8214-7.33040.22521390.18952628X-RAY DIFFRACTION100
7.3304-49.10170.23741390.20322656X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -73.9868 Å / Origin y: 46.2035 Å / Origin z: -14.4718 Å
111213212223313233
T0.3406 Å2-0.0004 Å20.0095 Å2-0.3033 Å2-0.0312 Å2--0.4032 Å2
L0.5753 °2-0.0194 °20.0107 °2-0.5254 °2-0.0039 °2--0.5569 °2
S0.0686 Å °-0.1146 Å °-0.0033 Å °0.1117 Å °0.0243 Å °-0.0623 Å °0.0195 Å °0.0414 Å °-0.0923 Å °
Refinement TLS groupSelection details: all

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