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- PDB-6uh7: EV-A71 strain 11316 complexed with MADAL compound 30 -

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Basic information

Entry
Database: PDB / ID: 6uh7
TitleEV-A71 strain 11316 complexed with MADAL compound 30
Components
  • VP1
  • VP2
  • VP3
  • VP4
KeywordsVIRUS / Enterovirus / 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 / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / symbiont-mediated suppression of host gene expression ...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 / symbiont-mediated suppression of host gene expression / nucleoside-triphosphate phosphatase / channel activity / viral capsid / monoatomic ion transmembrane transport / 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 / host cell nucleus / virion attachment to host cell / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / metal ion binding
Similarity search - Function
Jelly Rolls - #20 / Picornavirus coat protein / 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 ...Jelly Rolls - #20 / Picornavirus coat protein / 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) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / 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 / Jelly Rolls / 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 / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
SPHINGOSINE / Genome polyprotein / Genome polyprotein / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesEnterovirus A71
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.87 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, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

Movie
  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
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Structure viewerMolecule:
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Assembly

Deposited unit
A: VP1
B: VP2
C: VP3
D: VP4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,9025
Polymers94,6024
Non-polymers2991
Water00
1
A: VP1
B: VP2
C: VP3
D: VP4
hetero molecules
x 60


Theoretical massNumber of molelcules
Total (without water)5,694,119300
Polymers5,676,150240
Non-polymers17,97060
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: VP1
B: VP2
C: VP3
D: VP4
hetero molecules
x 5


  • icosahedral pentamer
  • 475 kDa, 20 polymers
Theoretical massNumber of molelcules
Total (without water)474,51025
Polymers473,01220
Non-polymers1,4975
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: VP1
B: VP2
C: VP3
D: VP4
hetero molecules
x 6


  • icosahedral 23 hexamer
  • 569 kDa, 24 polymers
Theoretical massNumber of molelcules
Total (without water)569,41230
Polymers567,61524
Non-polymers1,7976
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein VP1


Mass: 32748.754 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Enterovirus A71 / References: UniProt: D4QGA8
#2: Protein VP2


Mass: 27812.250 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Enterovirus A71 / References: UniProt: I6W7A3
#3: Protein VP3


Mass: 26540.332 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Enterovirus A71
References: UniProt: A0A0E3SXU7, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#4: Protein VP4


Mass: 7501.162 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Enterovirus A71
References: UniProt: E9RGA0, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#5: Chemical ChemComp-SPH / SPHINGOSINE


Mass: 299.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H37NO2
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Enterovirus A71 / Type: VIRUS / Entity ID: #1-#4 / Source: NATURAL
Source (natural)Organism: Enterovirus A71
Details of virusEmpty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 44 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30452 / Symmetry type: POINT

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