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- EMDB-0943: Structure of Enterovirus 71 in complex with NLD-22 -

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Basic information

Entry
Database: EMDB / ID: EMD-0943
TitleStructure of Enterovirus 71 in complex with NLD-22
Map data
Sample
  • Virus: Human enterovirus 71
    • Protein or peptide: Capsid protein VP1
    • Protein or peptide: Capsid protein VP2
    • Protein or peptide: Capsid protein VP3
    • Protein or peptide: Capsid protein VP4
  • Ligand: 1-(2-azanylpyridin-4-yl)-3-[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentyl]imidazolidin-2-one
KeywordsInhibitor / VIRUS
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 / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase ...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 / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / symbiont-mediated suppression of host gene expression / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription / virion attachment to host cell / structural molecule activity / 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 / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesHuman enterovirus 71
Methodsingle particle reconstruction / cryo EM / Resolution: 3.264 Å
AuthorsZhang M / Sun Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2017YFC840300 China
CitationJournal: J Med Chem / Year: 2020
Title: Design, Synthesis, and Evaluation of Novel Enterovirus 71 Inhibitors as Therapeutic Drug Leads for the Treatment of Human Hand, Foot, and Mouth Disease.
Authors: Min Zhang / Ying Wang / Wanli He / Yao Sun / Yan Guo / Weilong Zhong / Qiang Gao / Mingyang Liao / Xiangxi Wang / Yan Cai / Yu Guo / Zihe Rao /
Abstract: Human hand, foot, and mouth disease (HFMD) is a serious public health threat with high infection rates in children and infants who reside in Asia and the Pacific regions, and no effective drugs are ...Human hand, foot, and mouth disease (HFMD) is a serious public health threat with high infection rates in children and infants who reside in Asia and the Pacific regions, and no effective drugs are currently available. Enterovirus 71 (EV71) and coxsackievirus A16 are the major etiological pathogens. Based on an essential hydrophobic pocket on the viral capsid protein VP1, we designed and synthesized a series of small molecular weight compounds as inhibitors of EV71. A potential drug candidate named exhibited excellent antiviral activity (with an EC of 5.056 nM and a 100% protection rate for mice at a dose of 20 mg/kg) and low toxicity. had a favorable pharmacokinetic profile. High-resolution cryo-electron microscopy structural analysis confirmed bound to the hydrophobic pocket in VP1 to block viral infection. In general, was indicated to be a promising potential drug candidate for the treatment of HFMD.
History
DepositionJan 13, 2020-
Header (metadata) releaseMar 11, 2020-
Map releaseMar 11, 2020-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.1
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  • Surface view colored by radius
  • Surface level: 0.1
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  • Surface view with fitted model
  • Atomic models: PDB-6lqd
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6lqd
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0943.png

Downloads & links

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Map

FileDownload / File: emd_0943.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.36 Å
Density
Contour LevelBy AUTHOR: 0.1 / Movie #1: 0.1
Minimum - Maximum-0.2724266 - 0.36459288
Average (Standard dev.)0.0011175595 (±0.021503918)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 489.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.361.361.36
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z489.600489.600489.600
α/β/γ90.00090.00090.000
start NX/NY/NZ-200-200-200
NX/NY/NZ401401401
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-0.2720.3650.001

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Supplemental data

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Sample components

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Entire : Human enterovirus 71

EntireName: Human enterovirus 71
Components
  • Virus: Human enterovirus 71
    • Protein or peptide: Capsid protein VP1
    • Protein or peptide: Capsid protein VP2
    • Protein or peptide: Capsid protein VP3
    • Protein or peptide: Capsid protein VP4
  • Ligand: 1-(2-azanylpyridin-4-yl)-3-[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentyl]imidazolidin-2-one

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Supramolecule #1: Human enterovirus 71

SupramoleculeName: Human enterovirus 71 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 / NCBI-ID: 39054 / Sci species name: Human enterovirus 71 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No

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Macromolecule #1: Capsid protein VP1

MacromoleculeName: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Human enterovirus 71
Molecular weightTheoretical: 32.727891 KDa
SequenceString: GDRVADVIES SIGDSVSRAL THALPAPTGQ NTQVSSHRLD TGKVPALQAA EIGASSNASD ESMIETRCVL NSHSTAETTL DSFFSRAGL VGEIDLPLKG TTNPNGYANW DIDITGYAQM RRKVELFTYM RFDAEFTFVA CTPTGEVVPQ LLQYMFVPPG A PKPDSRES ...String:
GDRVADVIES SIGDSVSRAL THALPAPTGQ NTQVSSHRLD TGKVPALQAA EIGASSNASD ESMIETRCVL NSHSTAETTL DSFFSRAGL VGEIDLPLKG TTNPNGYANW DIDITGYAQM RRKVELFTYM RFDAEFTFVA CTPTGEVVPQ LLQYMFVPPG A PKPDSRES LAWQTATNPS VFVKLSDPPA QVSVPFMSPA SAYQWFYDGY PTFGEHKQEK DLEYGAMPNN MMGTFSVRTV GT SKSKYPL VVRIYMRMKH VRAWIPRPMR NQNYLFKANP NYAGNSIKPT GASRTAITTL

UniProtKB: Genome polyprotein

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Macromolecule #2: Capsid protein VP2

MacromoleculeName: Capsid protein VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Human enterovirus 71
Molecular weightTheoretical: 27.74016 KDa
SequenceString: SPSAEACGYS DRVAQLTIGN STITTQEAAN IIVGYGEWPS YCSDSDATAV DKPTRPDVSV NRFYTLDTKL WEKSSKGWYW KFPDVLTET GVFGQNAQFH YLYRSGFCIH VQCNASKFHQ GALLVAVLPE YVIGTVAGGT GTEDTHPPYK QTQPGADGFE L QHPYVLDA ...String:
SPSAEACGYS DRVAQLTIGN STITTQEAAN IIVGYGEWPS YCSDSDATAV DKPTRPDVSV NRFYTLDTKL WEKSSKGWYW KFPDVLTET GVFGQNAQFH YLYRSGFCIH VQCNASKFHQ GALLVAVLPE YVIGTVAGGT GTEDTHPPYK QTQPGADGFE L QHPYVLDA GIPISQLTVC PHQWINLRTN NCATIIVPYI NALPFDSALN HCNFGLLVVP ISPLDYDQGA TPVIPITITL AP MCSEFAG LRQAVTQ

UniProtKB: Genome polyprotein

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Macromolecule #3: Capsid protein VP3

MacromoleculeName: Capsid protein VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Human enterovirus 71
Molecular weightTheoretical: 26.468225 KDa
SequenceString: GFPTELKPGT NQFLTTDDGV SAPILPNFHP TPCIHIPGEV RNLLELCQVE TILEVNNVPT NATSLMERLR FPVSAQAGKG ELCAVFRAD PGRNGPWQST LLGQLCGYYT QWSGSLEVTF MFTGSFMATG KMLIAYTPPG GPLPKDRATA MLGTHVIWDF G LQSSVTLV ...String:
GFPTELKPGT NQFLTTDDGV SAPILPNFHP TPCIHIPGEV RNLLELCQVE TILEVNNVPT NATSLMERLR FPVSAQAGKG ELCAVFRAD PGRNGPWQST LLGQLCGYYT QWSGSLEVTF MFTGSFMATG KMLIAYTPPG GPLPKDRATA MLGTHVIWDF G LQSSVTLV IPWISNTHYR AHARDGVFDY YTTGLVSIWY QTNYVVPIGA PNTAYIIALA AAQKNFTMKL CKDASDILQT GT IQ

UniProtKB: Genome polyprotein

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Macromolecule #4: Capsid protein VP4

MacromoleculeName: Capsid protein VP4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Human enterovirus 71
Molecular weightTheoretical: 7.501162 KDa
SequenceString:
MGSQVSTQRS GSHENSNSAT EGSTINYTTI NYYKDSYAAT AGKQSLKQDP DKFANPVKDI FTEMAAPLK

UniProtKB: Genome polyprotein

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Macromolecule #5: 1-(2-azanylpyridin-4-yl)-3-[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)p...

MacromoleculeName: 1-(2-azanylpyridin-4-yl)-3-[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentyl]imidazolidin-2-one
type: ligand / ID: 5 / Number of copies: 1 / Formula: EQ9
Molecular weightTheoretical: 422.48 Da
Chemical component information

ChemComp-EQ9:
1-(2-azanylpyridin-4-yl)-3-[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentyl]imidazolidin-2-one

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 35.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

9642

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.264 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 13185
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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