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- EMDB-23441: Structure of human SetD3 methyl-transferase in complex with 2A pr... -

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Basic information

Entry
Database: EMDB / ID: EMD-23441
TitleStructure of human SetD3 methyl-transferase in complex with 2A protease from Coxsackievirus B3
Map dataFrom cryosparc 2 non uniform refinement job, final map, filtered by FSC (3.5A), sharpened with b-factor of 180.
Sample
  • Complex: Ternary complex of Coxsackievirus B3 2A protease and human SetD3 methyltransferase
    • Protein or peptide: Protease 2A
    • Protein or peptide: Actin-histidine N-methyltransferase
  • Ligand: ZINC ION
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
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
Genome polyprotein / Actin-histidine N-methyltransferase
Similarity search - Component
Biological speciesCoxsackievirus B3 (strain Nancy) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsVerba KA / 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, 2021-
Header (metadata) releaseAug 10, 2022-
Map releaseAug 10, 2022-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_23441.png

Downloads & links

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Map

FileDownload / File: emd_23441.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFrom cryosparc 2 non uniform refinement job, final map, filtered by FSC (3.5A), sharpened with b-factor of 180.
Voxel sizeX=Y=Z: 0.835 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.7839078 - 3.1394837
Average (Standard dev.)0.00083502964 (±0.07885853)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 213.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_23441_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_23441_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_23441_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of Coxsackievirus B3 2A protease and human SetD3 ...

EntireName: Ternary complex of Coxsackievirus B3 2A protease and human SetD3 methyltransferase
Components
  • Complex: Ternary complex of Coxsackievirus B3 2A protease and human SetD3 methyltransferase
    • Protein or peptide: Protease 2A
    • Protein or peptide: Actin-histidine N-methyltransferase
  • Ligand: ZINC ION
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE

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Supramolecule #1: Ternary complex of Coxsackievirus B3 2A protease and human SetD3 ...

SupramoleculeName: Ternary complex of Coxsackievirus B3 2A protease and human SetD3 methyltransferase
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Coxsackievirus B3 (strain Nancy)
Molecular weightTheoretical: 84 KDa

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Macromolecule #1: Protease 2A

MacromoleculeName: Protease 2A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Coxsackievirus B3 (strain Nancy) / Strain: Nancy
Molecular weightTheoretical: 16.584482 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SNAMGQQSGA VYVGNYRVVN RHLATSADWQ NCVWESYNRD LLVSTTTAHG CDIIARCQCT TGVYFCASKN KHYPISFEGP GLVEVQESE YYPRRYQSHV LLAAGFSEPG DAGGILRCEH GVIGIVTMGG EGVVGFADIR DLLWLEDDAM EQ

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Macromolecule #2: Actin-histidine N-methyltransferase

MacromoleculeName: Actin-histidine N-methyltransferase / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: protein-histidine N-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.483117 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SNAGKKSRVK TQKSGTGATA TVSPKEILNL TSELLQKCSS PAPGPGKEWE EYVQIRTLVE KIRKKQKGLS VTFDGKREDY FPDLMKWAS ENGASVEGFE MVNFKEEGFG LRATRDIKAE ELFLWVPRKL LMTVESAKNS VLGPLYSQDR ILQAMGNIAL A FHLLCERA ...String:
SNAGKKSRVK TQKSGTGATA TVSPKEILNL TSELLQKCSS PAPGPGKEWE EYVQIRTLVE KIRKKQKGLS VTFDGKREDY FPDLMKWAS ENGASVEGFE MVNFKEEGFG LRATRDIKAE ELFLWVPRKL LMTVESAKNS VLGPLYSQDR ILQAMGNIAL A FHLLCERA SPNSFWQPYI QTLPSEYDTP LYFEEDEVRY LQSTQAIHDV FSQYKNTARQ YAYFYKVIQT HPHANKLPLK DS FTYEDYR WAVSSVMTRQ NQIPTEDGSR VTLALIPLWD MCNHTNGLIT TGYNLEDDRC ECVALQDFRA GEQIYIFYGT RSN AEFVIH SGFFFDNNSH DRVKIKLGVS KSDRLYAMKA EVLARAGIPT SSVFALHFTE PPISAQLLAF LRVFCMTEEE LKEH LLGDS AIDRIFTLGN SEFPVSWDNE VKLWTFLEDR ASLLLKTYKT TIEEDKSVLK NHDLSVRAKM AIKLRLGEKE ILEKA VKSA AVNREYYRQQ MEEKAPLPKY EESNLGLLES SVGDSRLPLV LRNLEEEAGV QDALNIREAI SKAKATENGL VNGENS IPN GTRSENESLN QESKRAVEDA KGSSSDSTAG VKE

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: S-ADENOSYL-L-HOMOCYSTEINE

MacromoleculeName: S-ADENOSYL-L-HOMOCYSTEINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: SAH
Molecular weightTheoretical: 384.411 Da
Chemical component information

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine

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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

Concentration0.34 mg/mL
BufferpH: 7.2
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMsodium chlorideNaClSodium chloride
1.0 mMTCEP
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR / Details: 17mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 1200 / Average exposure time: 6.0 sec. / Average electron dose: 68.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1100000
Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 2 / Avg.num./class: 75000 / Software - Name: cryoSPARC (ver. 2.14)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.14) / Number images used: 107000
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6mbk


Chain - Chain ID: A
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7lms:
Structure of human SetD3 methyl-transferase in complex with 2A protease from Coxsackievirus B3

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Atomic model buiding 2

Initial modelPDB ID:

4mg3


Chain - Chain ID: A
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7lms:
Structure of human SetD3 methyl-transferase in complex with 2A protease from Coxsackievirus B3

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