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- EMDB-0103: Identification of a druggable VP1-VP3 interprotomer pocket in the... -
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Open data
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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 | |||||||||
![]() | Coxsackievirus B3 Nancy in complex with a small-molecule inhibitor | |||||||||
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![]() | Inhibitor / ![]() ![]() | |||||||||
Function / homology | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Geraets JA / Flatt JW | |||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 55.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20.6 KB 20.6 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 14.5 KB | Display | ![]() |
Images | ![]() | 291.5 KB | ||
Filedesc metadata | ![]() | 6.6 KB | ||
Others | ![]() ![]() | 128.2 MB 128.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6gzvMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data size: 2.2 TB Data #1: Unaligned multi-frame micrographs of CVB3 in complex with a small molecular inhibitor [micrographs - single frame]) |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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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 |
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Sample components
-Entire : Coxsackievirus B3 (strain Nancy)
Entire | Name: ![]() ![]() |
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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: ![]() ![]() |
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: ![]() |
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Source (natural) | Organism: ![]() ![]() |
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: ![]() |
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Source (natural) | Organism: ![]() ![]() |
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: ![]() |
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Source (natural) | Organism: ![]() ![]() |
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: ![]() |
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Source (natural) | Organism: ![]() ![]() |
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 | ![]() |
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Aggregation state | particle |
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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 |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-6gzv: |