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- PDB-8q7c: Cryo-EM structure of Adenovirus C5 hexon -

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Basic information

Entry
Database: PDB / ID: 8q7c
TitleCryo-EM structure of Adenovirus C5 hexon
ComponentsHexon protein
KeywordsVIRUS / capsid protein / trimer
Function / homology
Function and homology information


T=25 icosahedral viral capsid / microtubule-dependent intracellular transport of viral material towards nucleus / 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
Biological speciesHuman adenovirus 5
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsZoll, S. / Dhillon, A.
Funding support Czech Republic, 1items
OrganizationGrant numberCountry
Not funded Czech Republic
CitationJournal: J Virol / Year: 2024
Title: Structural insights into the interaction between adenovirus C5 hexon and human lactoferrin.
Authors: Arun Dhillon / B David Persson / Alexander N Volkov / Hagen Sülzen / Alan Kádek / Petr Pompach / Sami Kereïche / Martin Lepšík / Katarina Danskog / Charlotte Uetrecht / Niklas Arnberg / Sebastian Zoll /
Abstract: Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human AdV species C types, such as HAdV-C5, utilize the Coxsackie-adenovirus receptor (CAR) for attachment ...Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human AdV species C types, such as HAdV-C5, utilize the Coxsackie-adenovirus receptor (CAR) for attachment and subsequently integrins for entry. CAR and integrins are however located deep within the tight junctions in the mucosa where they would not be easily accessible. Recently, a model for CAR-independent AdV entry was proposed. In this model, human lactoferrin (hLF), an innate immune protein, aids the viral uptake into epithelial cells by mediating interactions between the major capsid protein, hexon, and yet unknown host cellular receptor(s). However, a detailed understanding of the molecular interactions driving this mechanism is lacking. Here, we present a new cryo-EM structure of HAdV-5C hexon at high resolution alongside a hybrid structure of HAdV-5C hexon complexed with human lactoferrin (hLF). These structures reveal the molecular determinants of the interaction between hLF and HAdV-C5 hexon. hLF engages hexon primarily its N-terminal lactoferricin (Lfcin) region, interacting with hexon's hypervariable region 1 (HVR-1). Mutational analyses pinpoint critical Lfcin contacts and also identify additional regions within hLF that critically contribute to hexon binding. Our study sheds more light on the intricate mechanism by which HAdV-C5 utilizes soluble hLF/Lfcin for cellular entry. These findings hold promise for advancing gene therapy applications and inform vaccine development.
IMPORTANCE: Our study delves into the structural aspects of adenovirus (AdV) infections, specifically HAdV-C5 in the respiratory epithelium. It uncovers the molecular details of a novel pathway where ...IMPORTANCE: Our study delves into the structural aspects of adenovirus (AdV) infections, specifically HAdV-C5 in the respiratory epithelium. It uncovers the molecular details of a novel pathway where human lactoferrin (hLF) interacts with the major capsid protein, hexon, facilitating viral entry, and bypassing traditional receptors such as CAR and integrins. The study's cryo-EM structures reveal how hLF engages hexon, primarily through its N-terminal lactoferricin (Lfcin) region and hexon's hypervariable region 1 (HVR-1). Mutational analyses identify critical Lfcin contacts and other regions within hLF vital for hexon binding. This structural insight sheds light on HAdV-C5's mechanism of utilizing soluble hLF/Lfcin for cellular entry, holding promise for gene therapy and vaccine development advancements in adenovirus research.
History
DepositionAug 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 27, 2024Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hexon protein
B: Hexon protein
C: Hexon protein


Theoretical massNumber of molelcules
Total (without water)324,3233
Polymers324,3233
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 108107.617 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Human adenovirus 5 / References: UniProt: P04133

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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: Ternary complex of adenovirus C5 hexon polypeptides / Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightValue: 0.324 MDa / Experimental value: NO
Source (natural)Organism: Human adenovirus 5
Buffer solutionpH: 7.2
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 FIELDBright-field microscopy / Nominal defocus max: 2600 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53396 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 166.96 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004321930
ELECTRON MICROSCOPYf_angle_d0.519529838
ELECTRON MICROSCOPYf_chiral_restr0.04193174
ELECTRON MICROSCOPYf_plane_restr0.00333906
ELECTRON MICROSCOPYf_dihedral_angle_d3.79222952

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