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- PDB-8x8q: Structure of enterovirus protease in complex host factor -

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Basic information

Entry
Database: PDB / ID: 8x8q
TitleStructure of enterovirus protease in complex host factor
Components
  • 2A protein (Fragment)
  • Actin-histidine N-methyltransferase
KeywordsCELL CYCLE / host protein / VIRAL PROTEIN / CELL INVASION
Function / homology
Function and homology information


protein-histidine N-methyltransferase / peptidyl-histidine methylation / regulation of uterine smooth muscle contraction / protein-L-histidine N-tele-methyltransferase activity / actin modification / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / positive regulation of muscle cell differentiation / cysteine-type peptidase activity / viral process ...protein-histidine N-methyltransferase / peptidyl-histidine methylation / regulation of uterine smooth muscle contraction / protein-L-histidine N-tele-methyltransferase activity / actin modification / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / positive regulation of muscle cell differentiation / cysteine-type peptidase activity / viral process / PKMTs methylate histone lysines / actin binding / RNA polymerase II-specific DNA-binding transcription factor binding / host cell cytoplasm / transcription coactivator activity / chromatin / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / proteolysis / nucleoplasm / metal ion binding / cytoplasm
Similarity search - Function
Actin-histidine N-methyltransferase SETD3 / SETD3, SET domain / SETD3 actin-histidine N-methyltransferase (EC 2.1.1.85) family profile. / Rubisco LSMT, substrate-binding domain / Rubisco LSMT, substrate-binding domain superfamily / Rubisco LSMT substrate-binding / SET domain superfamily / SET domain / SET domain profile. / SET domain ...Actin-histidine N-methyltransferase SETD3 / SETD3, SET domain / SETD3 actin-histidine N-methyltransferase (EC 2.1.1.85) family profile. / Rubisco LSMT, substrate-binding domain / Rubisco LSMT, substrate-binding domain superfamily / Rubisco LSMT substrate-binding / SET domain superfamily / SET domain / SET domain profile. / SET domain / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Actin-histidine N-methyltransferase / 2A protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterovirus A71
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsGao, X. / Cui, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction.
Authors: Xiaopan Gao / Bei Wang / Kaixiang Zhu / Linyue Wang / Bo Qin / Kun Shang / Wei Ding / Jianwei Wang / Sheng Cui /
Abstract: SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has ...SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A's ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.
History
DepositionNov 28, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 29, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Actin-histidine N-methyltransferase
F: 2A protein (Fragment)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,9703
Polymers83,9042
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Actin-histidine N-methyltransferase


Mass: 67342.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SETD3 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q86TU7
#2: Protein 2A protein (Fragment)


Mass: 16562.418 Da / Num. of mol.: 1 / Mutation: C110A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterovirus A71 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: R9YK28
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: enterovirus protease in complex host factor / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Enterovirus A7139054
21Homo sapiens (human)9606
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 8
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1800 nm / Calibrated defocus min: 1800 nm / Calibrated defocus max: 2500 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 80 K / Temperature (min): 70 K
Image recordingElectron dose: 66 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2211651
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 603524 / Num. of class averages: 66 / Symmetry type: POINT
Atomic model buildingB value: 103 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: Correlation coefficient
Atomic model buildingPDB-ID: 3w95

3w95


Accession code: 3w95 / Source name: PDB / Type: experimental model

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