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- PDB-7lms: Structure of human SetD3 methyl-transferase in complex with 2A pr... -

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Basic information

Entry
Database: PDB / ID: 7lms
TitleStructure of human SetD3 methyl-transferase in complex with 2A protease from Coxsackievirus B3
Components
  • Actin-histidine N-methyltransferase
  • Protease 2A
KeywordsVIRAL PROTEIN / Methyltransferase / viral protease
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 / : / symbiont-mediated perturbation of host gene expression / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / positive regulation of muscle cell differentiation ...protein-histidine N-methyltransferase / peptidyl-histidine methylation / regulation of uterine smooth muscle contraction / protein-L-histidine N-tele-methyltransferase activity / actin modification / : / symbiont-mediated perturbation of host gene expression / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / positive regulation of muscle cell differentiation / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / PKMTs methylate histone lysines / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / actin binding / RNA polymerase II-specific DNA-binding transcription factor binding / RNA helicase activity / DNA replication / transcription coactivator activity / induction by virus of host autophagy / RNA-directed RNA polymerase / symbiont-mediated suppression of host gene expression / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / host cell nucleus / chromatin / virion attachment to host cell / structural molecule activity / positive regulation of DNA-templated transcription / ATP hydrolysis activity / positive regulation of transcription by RNA polymerase II / proteolysis / RNA binding / nucleoplasm / ATP binding / membrane / 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 / Picornavirus coat protein VP4 superfamily / SET domain superfamily / SET domain / SET domain profile. ...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 / Picornavirus coat protein VP4 superfamily / SET domain superfamily / SET domain / SET domain profile. / SET domain / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / Genome polyprotein / Actin-histidine N-methyltransferase
Similarity search - Component
Biological speciesCoxsackievirus B3
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsVerba, K.A. / Schulze-Gahmen, U.
CitationJournal: Nat Commun / Year: 2022
Title: Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.
Authors: Christine E Peters / Ursula Schulze-Gahmen / Manon Eckhardt / Gwendolyn M Jang / Jiewei Xu / Ernst H Pulido / Conner Bardine / Charles S Craik / Melanie Ott / Or Gozani / Kliment A Verba / ...Authors: Christine E Peters / Ursula Schulze-Gahmen / Manon Eckhardt / Gwendolyn M Jang / Jiewei Xu / Ernst H Pulido / Conner Bardine / Charles S Craik / Melanie Ott / Or Gozani / Kliment A Verba / Ruth Hüttenhain / Jan E Carette / Nevan J Krogan /
Abstract: Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this ...Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.
History
DepositionFeb 5, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Refinement description
Category: citation / citation_author / pdbx_initial_refinement_model
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protease 2A
A: Actin-histidine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,5174
Polymers84,0682
Non-polymers4502
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protease 2A


Mass: 16584.482 Da / Num. of mol.: 1 / Mutation: C107A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus B3 (strain Nancy) / Strain: Nancy / Production host: Escherichia coli (E. coli) / References: UniProt: P03313, picornain 2A
#2: Protein Actin-histidine N-methyltransferase / SET domain-containing protein 3 / hSETD3


Mass: 67483.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SETD3, C14orf154 / Production host: Escherichia coli (E. coli)
References: UniProt: Q86TU7, protein-histidine N-methyltransferase
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
Has ligand of interestN

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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 Coxsackievirus B3 2A protease and human SetD3 methyltransferase
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.084 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Coxsackievirus B3 (strain Nancy)562
21Homo sapiens (human)9606
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.2
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2150 mMsodium chlorideNaClSodium chloride1
31 mMTCEP1
SpecimenConc.: 0.34 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 17mA / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K

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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 FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 68 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1200

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Processing

EM software
IDNameVersionCategoryDetailsFitting-ID
2SerialEMimage acquisition
4cryoSPARC2.14CTF correction
7Rosetta3model fittingFastRelax Torsion1
11cryoSPARC2.14classification
12cryoSPARC2.143D reconstruction
20Rosetta3model refinement1
21PHENIX1.18model refinement1
22ISOLDE1.01model refinement1
23Rosetta3model fittingFastRelax Torsion2
24Rosetta3model refinement2
25PHENIX1.18model refinement2
26ISOLDE1.01model refinement2
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1100000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107000 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model building
IDProtocolSpace
1FLEXIBLE FITREAL
2FLEXIBLE FITREAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
16MBK

6mbk

A1
24MG3

4mg3

A2

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