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Yorodumi- EMDB-0103: Identification of a druggable VP1-VP3 interprotomer pocket in the... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-0103 | |||||||||
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Title | Identification of a druggable VP1-VP3 interprotomer pocket in the capsid of enteroviruses | |||||||||
Map data | Coxsackievirus B3 Nancy in complex with a small-molecule inhibitor | |||||||||
Sample |
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Keywords | Inhibitor / complex / virus | |||||||||
Function / homology | Function and homology information symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host transcription / 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 ...symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host transcription / 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 / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / DNA replication / RNA helicase activity / induction by virus of host autophagy / cysteine-type endopeptidase activity / RNA-directed RNA polymerase / viral RNA genome replication / virus-mediated perturbation of host defense response / RNA-dependent RNA polymerase activity / DNA-templated transcription / host cell nucleus / virion attachment to host cell / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / membrane / metal ion binding Similarity search - Function | |||||||||
Biological species | Coxsackievirus B3 (strain Nancy) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.0 Å | |||||||||
Authors | Geraets JA / Flatt JW | |||||||||
Funding support | Finland, 1 items
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Citation | Journal: PLoS Biol / Year: 2019 Title: A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses. Authors: Rana Abdelnabi / James A Geraets / Yipeng Ma / Carmen Mirabelli / Justin W Flatt / Aušra Domanska / Leen Delang / Dirk Jochmans / Timiri Ajay Kumar / Venkatesan Jayaprakash / Barij Nayan ...Authors: Rana Abdelnabi / James A Geraets / Yipeng Ma / Carmen Mirabelli / Justin W Flatt / Aušra Domanska / Leen Delang / Dirk Jochmans / Timiri Ajay Kumar / Venkatesan Jayaprakash / Barij Nayan Sinha / Pieter Leyssen / Sarah J Butcher / Johan Neyts / Abstract: Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral ...Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_0103.map.gz | 55.9 MB | EMDB map data format | |
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Header (meta data) | emd-0103-v30.xml emd-0103.xml | 20.6 KB 20.6 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_0103_fsc.xml | 14.5 KB | Display | FSC data file |
Images | emd_0103.png | 291.5 KB | ||
Filedesc metadata | emd-0103.cif.gz | 6.6 KB | ||
Others | emd_0103_half_map_1.map.gz emd_0103_half_map_2.map.gz | 128.2 MB 128.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-0103 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0103 | HTTPS FTP |
-Validation report
Summary document | emd_0103_validation.pdf.gz | 422.3 KB | Display | EMDB validaton report |
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Full document | emd_0103_full_validation.pdf.gz | 421.5 KB | Display | |
Data in XML | emd_0103_validation.xml.gz | 17.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0103 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0103 | HTTPS FTP |
-Related structure data
Related structure data | 6gzvMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10199 (Title: Identification of a druggable VP1-VP3 interprotomer pocket in the capsid of enteroviruses Data size: 2.2 TB Data #1: Unaligned multi-frame micrographs of CVB3 in complex with a small molecular inhibitor [micrographs - single frame]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_0103.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Coxsackievirus B3 Nancy in complex with a small-molecule inhibitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.048 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: #2
File | emd_0103_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_0103_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Coxsackievirus B3 (strain Nancy)
Entire | Name: Coxsackievirus B3 (strain Nancy) |
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Components |
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-Supramolecule #1: Coxsackievirus B3 (strain Nancy)
Supramolecule | Name: Coxsackievirus B3 (strain Nancy) / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 Details: Coxsackievirus B3 (strain Nancy) NCBI Taxonomy ID: 103903 Full, non-enveloped virion from natural source Diameter: ~314A Triangulation: 1 (pT3) Benzene sulfonamide derivative Molecular ...Details: Coxsackievirus B3 (strain Nancy) NCBI Taxonomy ID: 103903 Full, non-enveloped virion from natural source Diameter: ~314A Triangulation: 1 (pT3) Benzene sulfonamide derivative Molecular weight: 422Da Binding sites on capsid: 60 NCBI-ID: 103903 / Sci species name: Coxsackievirus B3 (strain Nancy) / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No |
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Host (natural) | Organism: Homo sapiens (human) |
Virus shell | Shell ID: 1 / Diameter: 314.0 Å / T number (triangulation number): 1 |
-Macromolecule #1: Capsid protein VP1
Macromolecule | Name: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A |
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Source (natural) | Organism: Coxsackievirus B3 (strain Nancy) / Strain: Nancy |
Molecular weight | Theoretical: 31.639438 KDa |
Sequence | String: GPVEDAITAA IGRVADTVGT GPTNSEAIPA LTAAETGHTS QVVPGDTMQT RHVKNYHSRS ESTIENFLCR SACVYFTEYK NSGAKRYAE WVLTPRQAAQ LRRKLEFFTY VRFDLELTFV ITSTQQPSTT QNQDAQILTH QIMYVPPGGP VPDKVDSYVW Q TSTNPSVF ...String: GPVEDAITAA IGRVADTVGT GPTNSEAIPA LTAAETGHTS QVVPGDTMQT RHVKNYHSRS ESTIENFLCR SACVYFTEYK NSGAKRYAE WVLTPRQAAQ LRRKLEFFTY VRFDLELTFV ITSTQQPSTT QNQDAQILTH QIMYVPPGGP VPDKVDSYVW Q TSTNPSVF WTEGNAPPRM SIPFLSIGNA YSNFYDGWSE FSRNGVYGIN TLNNMGTLYA RHVNAGSTGP IKSTIRIYFK PK HVKAWIP RPPRLCQYEK AKNVNFQPSG VTTTRQSITT MTNTGAF UniProtKB: Genome polyprotein |
-Macromolecule #2: Capsid protein VP2
Macromolecule | Name: Capsid protein VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A |
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Source (natural) | Organism: Coxsackievirus B3 (strain Nancy) / Strain: Nancy |
Molecular weight | Theoretical: 28.836502 KDa |
Sequence | String: SPTVEECGYS DRARSITLGN STITTQECAN VVVGYGVWPD YLKDSEATAE DQPTQPDVAT CRFYTLDSVQ WQKTSPGWWW KLPDALSNL GLFGQNMQYH YLGRTGYTVH VQCNASKFHQ GCLLVVCVPE AEMGCATLDN TPSSAELLGG DTAKEFADKP V ASGSNKLV ...String: SPTVEECGYS DRARSITLGN STITTQECAN VVVGYGVWPD YLKDSEATAE DQPTQPDVAT CRFYTLDSVQ WQKTSPGWWW KLPDALSNL GLFGQNMQYH YLGRTGYTVH VQCNASKFHQ GCLLVVCVPE AEMGCATLDN TPSSAELLGG DTAKEFADKP V ASGSNKLV QRVVYNAGMG VGVGNLTIFP HQWINLRTNN SATIVMPYTN SVPMDNMFRH NNVTLMVIPF VPLDYCPGST TY VPITVTI APMCAEYNGL RLAGHQ UniProtKB: Genome polyprotein |
-Macromolecule #3: Capsid protein VP3
Macromolecule | Name: Capsid protein VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A |
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Source (natural) | Organism: Coxsackievirus B3 (strain Nancy) / Strain: Nancy |
Molecular weight | Theoretical: 26.195727 KDa |
Sequence | String: GLPTMNTPGS CQFLTSDDFQ SPSAMPQYDV TPEMRIPGEV KNLMEIAEVD SVVPVQNVGE KVNSMEAYQI PVRSNEGSGT QVFGFPLQP GYSSVFSRTL LGEILNYYTH WSGSIKLTFM FCGSAMATGK FLLAYSPPGA GAPTKRVDAM LGTHVIWDVG L QSSCVLCI ...String: GLPTMNTPGS CQFLTSDDFQ SPSAMPQYDV TPEMRIPGEV KNLMEIAEVD SVVPVQNVGE KVNSMEAYQI PVRSNEGSGT QVFGFPLQP GYSSVFSRTL LGEILNYYTH WSGSIKLTFM FCGSAMATGK FLLAYSPPGA GAPTKRVDAM LGTHVIWDVG L QSSCVLCI PWISQTHYRF VASDEYTAGG FITCWYQTNI VVPADAQSSC YIMCFVSACN DFSVRLLKDT PFISQQNFFQ UniProtKB: Genome polyprotein |
-Macromolecule #4: Capsid protein VP4
Macromolecule | Name: Capsid protein VP4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A |
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Source (natural) | Organism: Coxsackievirus B3 (strain Nancy) / Strain: Nancy |
Molecular weight | Theoretical: 7.580377 KDa |
Sequence | String: MGAQVSTQKT GAHETRLNAS GNSIIHYTNI NYYKDAASNS ANRQDFTQDP GKFTEPVKDI MIKSLPALN UniProtKB: Genome polyprotein |
-Macromolecule #5: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]b...
Macromolecule | Name: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid type: ligand / ID: 5 / Number of copies: 1 / Formula: FHK |
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Molecular weight | Theoretical: 422.411 Da |
Chemical component information | ChemComp-FHK: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 Component:
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Vitrification | Cryogen name: ETHANE / Instrument: HOMEMADE PLUNGER | |||||||||
Details | Inhibitor was added at 2500:1 molar ratio to purified CVB3 and incubated for 1h at 37C |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | PDB-6gzv: |