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- EMDB-20768: EV-A71 strain 11316 complexed with MADAL compound 22 -

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Basic information

Entry
Database: EMDB / ID: EMD-20768
TitleEV-A71 strain 11316 complexed with MADAL compound 22
Map dataCryo EM map of enterovirus A71 strain 11316 complexed with MADAL compound 22
Sample
  • Virus: Enterovirus A71
    • Protein or peptide: VP1
    • Protein or peptide: VP2
    • Protein or peptide: VP3
    • Protein or peptide: VP4
  • Ligand: SPHINGOSINE
KeywordsEnterovirus / VIRUS / inhibitor
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 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 / cytoplasmic vesicle membrane / : ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 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 / cytoplasmic vesicle membrane / : / viral capsid / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / RNA helicase 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 / structural molecule activity / virion attachment to host cell / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / metal ion binding
Similarity search - Function
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 ...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 / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesEnterovirus A71
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsLee H / Hafenstein S
CitationJournal: J Med Chem / Year: 2020
Title: Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors.
Authors: Belén Martínez-Gualda / Liang Sun / Olaia Martí-Marí / Sam Noppen / Rana Abdelnabi / Carol M Bator / Ernesto Quesada / Leen Delang / Carmen Mirabelli / Hyunwook Lee / Dominique Schols / ...Authors: Belén Martínez-Gualda / Liang Sun / Olaia Martí-Marí / Sam Noppen / Rana Abdelnabi / Carol M Bator / Ernesto Quesada / Leen Delang / Carmen Mirabelli / Hyunwook Lee / Dominique Schols / Johan Neyts / Susan Hafenstein / María-José Camarasa / Federico Gago / Ana San-Félix /
Abstract: Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for enterovirus EV71 infection for which ...Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for enterovirus EV71 infection for which no antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71. These compounds contain in their structure three or four tryptophan (Trp) residues linked to a central scaffold. Critical for anti-HIV/EV71 activity is the presence of extra phenyl rings, bearing one or two carboxylates, at the C2 position of the indole ring of each Trp residue. The most potent derivatives, and , inhibit early steps of the replicative cycles of HIV-1 and EV-A71 by interacting with their respective viral surfaces (glycoprotein gp120 of HIV and the fivefold axis of the EV-A71 capsid). The high potency, low toxicity, facile chemical synthesis, and great opportunities for chemical optimization make them useful prototypes for future medicinal chemistry studies.
History
DepositionSep 26, 2019-
Header (metadata) releaseNov 27, 2019-
Map releaseDec 18, 2019-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6uh6
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6uh6
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20768.png

Downloads & links

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Map

FileDownload / File: emd_20768.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo EM map of enterovirus A71 strain 11316 complexed with MADAL compound 22
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 2.5 / Movie #1: 2.5
Minimum - Maximum-2.6347785 - 7.972097
Average (Standard dev.)0.000000002256429 (±1.0000001)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-210-210-210
Dimensions420420420
Spacing420420420
CellA=B=C: 462.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z420420420
origin x/y/z0.0000.0000.000
length x/y/z462.000462.000462.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-210-210-210
NC/NR/NS420420420
D min/max/mean-2.6357.9720.000

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Supplemental data

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Additional map: Sharpened map of the EV-A71-MADAL 22 complex

Fileemd_20768_additional.map
AnnotationSharpened map of the EV-A71-MADAL 22 complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Enterovirus A71

EntireName: Enterovirus A71
Components
  • Virus: Enterovirus A71
    • Protein or peptide: VP1
    • Protein or peptide: VP2
    • Protein or peptide: VP3
    • Protein or peptide: VP4
  • Ligand: SPHINGOSINE

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Supramolecule #1: Enterovirus A71

SupramoleculeName: Enterovirus A71 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 / NCBI-ID: 39054 / Sci species name: Enterovirus A71 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No

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Macromolecule #1: VP1

MacromoleculeName: VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Enterovirus A71
Molecular weightTheoretical: 32.748754 KDa
SequenceString: GDRVADVIES SIGDSVSRAL TQALPAPTGQ NTQVSSHRLD TGEVPALQAA EIGASSNTSD ESMIETRCVL NSHSTAETTL DSFFSRAGL VGEIDLPLEG TTNPNGYANW DIDITGYAQM RRKVELFTYM RFDAEFTFVA CTPTGQVVPQ LLQYMFVPPG A PKPESRES ...String:
GDRVADVIES SIGDSVSRAL TQALPAPTGQ NTQVSSHRLD TGEVPALQAA EIGASSNTSD ESMIETRCVL NSHSTAETTL DSFFSRAGL VGEIDLPLEG TTNPNGYANW DIDITGYAQM RRKVELFTYM RFDAEFTFVA CTPTGQVVPQ LLQYMFVPPG A PKPESRES LAWQTATNPS VFVKLTDPPA QVSVPFMSPA SAYQWFYDGY PTFGEHKQEK DLEYGACPNN MMGTFSVRTV GS SKSKYPL VVRIYMRMKH VRAWIPRPMR NQNYLFKANP NYAGNSIKPT GTSRSAITTL

UniProtKB: Genome polyprotein

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Macromolecule #2: VP2

MacromoleculeName: VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Enterovirus A71
Molecular weightTheoretical: 26.946342 KDa
SequenceString: SDRVAQLTIG NSTITTQEAA NIIVGYGEWP SYCSDDDATA VDKPTRPDVS VNRFYTLDTK LWEKSSKGWY WKFPDVLTET GVFGQNAQF HYLYRSGFCI HVQCNASKFH QGALLVAILP EYVIGTVAGG TGTEDSHPPY KQTQPGADGF ELQHPYVLDA G IPISQLTV ...String:
SDRVAQLTIG NSTITTQEAA NIIVGYGEWP SYCSDDDATA VDKPTRPDVS VNRFYTLDTK LWEKSSKGWY WKFPDVLTET GVFGQNAQF HYLYRSGFCI HVQCNASKFH QGALLVAILP EYVIGTVAGG TGTEDSHPPY KQTQPGADGF ELQHPYVLDA G IPISQLTV CHHQRINLRT NNCATIIVPY MNTLPFDSAL NHCNFGLLVV PISPLDFDQG ATPVIPITIT LAPMCSEFAG LR QAVTQ

UniProtKB: Genome polyprotein

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Macromolecule #3: VP3

MacromoleculeName: VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Enterovirus A71
Molecular weightTheoretical: 26.540332 KDa
SequenceString: GFPTELKPGT NQFLTTDDGV SAPILPNFHP TPCIHIPGEV RNLLELCQVE TILEVNNVPT NATSLMERLR FPVSAQAGKG ELCAVFRAD PGRDGPWQST MLGQLCGYYT QWSGSLEVTF MFTGSFMATG KMLIAYTPPG GPLPKDRATA MLGTHVIWDF G LQSSVTLV ...String:
GFPTELKPGT NQFLTTDDGV SAPILPNFHP TPCIHIPGEV RNLLELCQVE TILEVNNVPT NATSLMERLR FPVSAQAGKG ELCAVFRAD PGRDGPWQST MLGQLCGYYT QWSGSLEVTF MFTGSFMATG KMLIAYTPPG GPLPKDRATA MLGTHVIWDF G LQSSVTLV IPWISNTHYR AHARDGVFDY YTTGLVSIWY QTNYVVPIGA PNTAYIIALA AAQKNFTMKL CKDTSHILQT AS IQ

UniProtKB: Genome polyprotein

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Macromolecule #4: VP4

MacromoleculeName: VP4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Enterovirus A71
Molecular weightTheoretical: 7.501162 KDa
SequenceString:
MGSQVSTQRS GSHENSNSAT EGSTINYTTI NYYKDSYAAT AGKQSLKQDP DKFANPVKDI FTEMAAPLK

UniProtKB: Genome polyprotein

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Macromolecule #5: SPHINGOSINE

MacromoleculeName: SPHINGOSINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: SPH
Molecular weightTheoretical: 299.492 Da
Chemical component information

ChemComp-SPH:
SPHINGOSINE / Sphingosine

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 44.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 42926

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