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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
KeywordsMethyltransferase / viral protease / VIRAL PROTEIN
Function / homology
Function and homology information


peptidyl-histidine methylation / regulation of uterine smooth muscle contraction / protein-histidine N-methyltransferase / protein-L-histidine N-tele-methyltransferase activity / actin modification / symbiont-mediated perturbation of host transcription / 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 ...peptidyl-histidine methylation / regulation of uterine smooth muscle contraction / protein-histidine N-methyltransferase / protein-L-histidine N-tele-methyltransferase activity / actin modification / symbiont-mediated perturbation of host transcription / 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 / PKMTs methylate histone lysines / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / actin binding / channel activity / monoatomic ion transmembrane transport / symbiont-mediated suppression of host NF-kappaB cascade / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / DNA replication / RNA helicase activity / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / nucleoplasm / ATP binding / membrane / 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 / SET domain superfamily ...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 / SET domain superfamily / SET domain profile. / SET domain / Picornavirus coat protein / 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) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / 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-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing 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.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 256 pix.
= 213.76 Å		0.84 Å/pix.
x 256 pix.
= 213.76 Å		0.84 Å/pix.
x 256 pix.
= 213.76 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
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

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Slices (1/2)
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Half map: #2

Fileemd_23441_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_23441_half_map_2.map
Projections & Slices
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Slices (1/2)
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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

UniProtKB: Genome polyprotein

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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

UniProtKB: Actin-histidine N-methyltransferase

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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

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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 chlorideNaCl
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
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1100000
Startup modelType of model: NONE
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
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 2 / Avg.num./class: 75000 / Software - Name: cryoSPARC (ver. 2.14)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6mbk


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
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 / Chain - Source name: PDB / Chain - Initial model type: experimental model
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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