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- EMDB-10222: Cryo-EM structure of rhinovirus-A89 -

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Basic information

Entry
Database: EMDB / ID: EMD-10222
TitleCryo-EM structure of rhinovirus-A89
Map data
Sample
  • Virus: Rhinovirus A
    • Protein or peptide: VP1 capsid protein
    • Protein or peptide: VP2 capsid protein
    • Protein or peptide: VP3 capsid protein
    • Protein or peptide: VP4 capsid protein
Function / homology
Function and homology information


: / positive stranded viral RNA replication / RNA-protein covalent cross-linking / : / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / ribonucleoside triphosphate phosphatase activity / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C ...: / positive stranded viral RNA replication / RNA-protein covalent cross-linking / : / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / ribonucleoside triphosphate phosphatase activity / 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 / viral capsid / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / host cell cytoplasm / RNA helicase activity / DNA replication / 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 / virion attachment to host cell / structural molecule activity / RNA binding / ATP binding / membrane / metal ion binding / cytoplasm
Similarity search - Function
Picornavirus coat protein VP4 superfamily / 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) ...Picornavirus coat protein VP4 superfamily / 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. / 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
Capsid protein VP0 / Genome polyprotein
Similarity search - Component
Biological speciesHRV-89 (virus) / Rhinovirus A
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWald J / Goessweiner-Mohr N / Blaas D / Pasin M
CitationJournal: Proc Natl Acad Sci U S A / Year: 2019
Title: Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site.
Authors: Jiri Wald / Marion Pasin / Martina Richter / Christin Walther / Neann Mathai / Johannes Kirchmair / Vadim A Makarov / Nikolaus Goessweiner-Mohr / Thomas C Marlovits / Irene Zanella / Antonio ...Authors: Jiri Wald / Marion Pasin / Martina Richter / Christin Walther / Neann Mathai / Johannes Kirchmair / Vadim A Makarov / Nikolaus Goessweiner-Mohr / Thomas C Marlovits / Irene Zanella / Antonio Real-Hohn / Nuria Verdaguer / Dieter Blaas / Michaela Schmidtke /
Abstract: Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 ...Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 Å with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 Å, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 Å was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
History
DepositionAug 14, 2019-
Header (metadata) releaseAug 28, 2019-
Map releaseSep 4, 2019-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
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  • Surface view colored by radius
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-6sk7
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6sk7
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_10222.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.97 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.048386812 - 0.08026486
Average (Standard dev.)0.00041190247 (±0.004740334)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-224-224-224
Dimensions450450450
Spacing450450450
CellA=B=C: 436.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.970.970.97
M x/y/z450450450
origin x/y/z0.0000.0000.000
length x/y/z436.500436.500436.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-224-224-224
NC/NR/NS450450450
D min/max/mean-0.0480.0800.000

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Supplemental data

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Mask #1

Fileemd_10222_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_10222_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #2

Fileemd_10222_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : Rhinovirus A

EntireName: Rhinovirus A
Components
  • Virus: Rhinovirus A
    • Protein or peptide: VP1 capsid protein
    • Protein or peptide: VP2 capsid protein
    • Protein or peptide: VP3 capsid protein
    • Protein or peptide: VP4 capsid protein

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Supramolecule #1: Rhinovirus A

SupramoleculeName: Rhinovirus A / type: virus / ID: 1 / Parent: 0 / Macromolecule list: all / NCBI-ID: 650130 / Sci species name: Rhinovirus A / Sci species strain: A89 / Virus type: VIRION / Virus isolate: SEROTYPE / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Virus shellShell ID: 1 / Name: VP1-4 / Diameter: 302.0 Å

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Macromolecule #1: VP1 capsid protein

MacromoleculeName: VP1 capsid protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: HRV-89 (virus)
Molecular weightTheoretical: 33.288102 KDa
SequenceString: NPVENYIDSV LNEVLVVPNI QPSTSVSSHA APALDAAETG HTSSVQPEDM IETRYVITDQ TRDETSIESF LGRSGCIAMI EFNTSSDKT EHDKIGKGFK TWKVSLQEMA QIRRKYELFT YTRFDSEITI VTAAAAQGND SGHIVLQFMY VPPGAPVPEK R DDYTWQSG ...String:
NPVENYIDSV LNEVLVVPNI QPSTSVSSHA APALDAAETG HTSSVQPEDM IETRYVITDQ TRDETSIESF LGRSGCIAMI EFNTSSDKT EHDKIGKGFK TWKVSLQEMA QIRRKYELFT YTRFDSEITI VTAAAAQGND SGHIVLQFMY VPPGAPVPEK R DDYTWQSG TNASVFWQEG QPYPRFTIPF MSIASAYYMF YDGYDGDSAA SKYGSVVTND MGTICVRIVT SNQKHDSNIV CR IYHKAKH IKAWCPRPPR AVAYQHTHST NYIPSNGEAT TQIKTRPDVF TVTNVGPSSM F

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Macromolecule #2: VP2 capsid protein

MacromoleculeName: VP2 capsid protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: HRV-89 (virus)
Molecular weightTheoretical: 29.422793 KDa
SequenceString: SPTVEACGYS DRLIQITRGD STITSQDTAN AVVAYGVWPS YLTPDDATAI DKPTQPDTSS NRFYTLDSRS WTSASSGWWW KLPDALKNM GIFGENMFYH FLGRSGYTIH VQCNSSKFHQ GLLIVAAIPE HQLASATSGN VSVGYNHTHP GEQGREVVPS R TSSDNKRP ...String:
SPTVEACGYS DRLIQITRGD STITSQDTAN AVVAYGVWPS YLTPDDATAI DKPTQPDTSS NRFYTLDSRS WTSASSGWWW KLPDALKNM GIFGENMFYH FLGRSGYTIH VQCNSSKFHQ GLLIVAAIPE HQLASATSGN VSVGYNHTHP GEQGREVVPS R TSSDNKRP SDDSWLNFDG TLLGNLPIYP HQYINLRTNN SATLILPYVN AVPMDSMLRH NNWSLVIIPI CPLQVQPGGT QS IPITVSI SPMFSEFSGP RSKVVFSTTQ

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Macromolecule #3: VP3 capsid protein

MacromoleculeName: VP3 capsid protein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: HRV-89 (virus)
Molecular weightTheoretical: 26.325994 KDa
SequenceString: GLPVMLTPGS GQFLTTDDTQ SPSAFPYFHP TKEIFIPGQV RNLIEMCQVD TLIPVNNTQE NVRSVNMYTV DLRTQVDLAK EVFSIPVDI ASQPLATTLI GELASYYTHW TGSLRFSFMF CGSASSTLKL LIAYTPPGVG KPKSRREAML GTHLVWDVGL Q STASLVVP ...String:
GLPVMLTPGS GQFLTTDDTQ SPSAFPYFHP TKEIFIPGQV RNLIEMCQVD TLIPVNNTQE NVRSVNMYTV DLRTQVDLAK EVFSIPVDI ASQPLATTLI GELASYYTHW TGSLRFSFMF CGSASSTLKL LIAYTPPGVG KPKSRREAML GTHLVWDVGL Q STASLVVP WVSASHFRFT TPDTYSSAGY ITCWYQTNFV VPDSTPDNAK MVCMVSACKD FCLRLARDTN LHTQEGVLTQ

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Macromolecule #4: VP4 capsid protein

MacromoleculeName: VP4 capsid protein / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: HRV-89 (virus)
Molecular weightTheoretical: 7.461104 KDa
SequenceString:
MGAQVSRQNV GTHSTQNSVS NGSSLNYFNI NYFKDAASSG ASRLDFSQDP SKFTDPVKDV LEKGIPTLQ

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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

BufferpH: 7.4 / Component:
NameConcentration
PBS
DMSODimethyl sulfoxide10.0 %
GridModel: Homemade / Material: COPPER / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 0.4 nm / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI POLARA 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 1-25 / Number real images: 5370 / Average exposure time: 5.0 sec. / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4.1)
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C60 (60 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 107054

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Atomic model buiding 1

Initial modelPDB ID:
DetailsRosetta: DiMaio, F. et al. Atomic-accuracy models from 4.5-A cryo-electron microscopy data with density-guided iterative local refinement. Nat. Meth (2015). doi:10.1038/nmeth.3286
RefinementSpace: REAL
Output model

PDB-6sk7:
Cryo-EM structure of rhinovirus-A89

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