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- PDB-8xpp: Crystal structure of the enterovirus 71 RdRP elongation complex w... -

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Basic information

Entry
Database: PDB / ID: 8xpp
TitleCrystal structure of the enterovirus 71 RdRP elongation complex with the nucleoside monophosphate form of compound HNC-1664 at product position -1 (post-translocation state)
Components
  • Genome polyprotein
  • RNA (17-MER)
  • RNA (35-MER)
KeywordsREPLICATION / enterovirus 71 / RNA-dependent RNA polymerase / elongation complex / nucleoside analog
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 / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport ...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 / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
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) ...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 / 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
RNA / RNA (> 10) / Genome polyprotein
Similarity search - Component
Biological speciesEnterovirus A71
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsZhong, Y. / Gong, P.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)2022YFC2303300 China
National Natural Science Foundation of China (NSFC)U23A20147 China
CitationJournal: Nat Commun / Year: 2024
Title: An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode.
Authors: Xiaoying Jia / Xuping Jing / Ming Li / Minli Gao / Yao Zhong / Entao Li / Yang Liu / Rui Li / Guoqiang Yao / Qiaojie Liu / Minmin Zhou / Yuxia Hou / Linfeng An / Yibao Hong / Shanshan Li / ...Authors: Xiaoying Jia / Xuping Jing / Ming Li / Minli Gao / Yao Zhong / Entao Li / Yang Liu / Rui Li / Guoqiang Yao / Qiaojie Liu / Minmin Zhou / Yuxia Hou / Linfeng An / Yibao Hong / Shanshan Li / Jiancun Zhang / Wei Wang / Kaiming Zhang / Peng Gong / Sandra Chiu /
Abstract: By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose- ...By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses. Importantly, treatment with HNC-1664 demonstrate anti-SARS-CoV-2 efficacy in infected K18-human ACE2 mice, with reduced viral titer and mortality, as well as improved lung injury. Enzymology data demonstrate that HNC-1664 inhibits RNA synthesis mainly at the pre-catalysis stage. The cryo-EM structures of HNC-1664-bound RdRP-RNA complexes from both SARS-CoV-2 and LASV reveal an unusual base pairing mode of HNC-1664 in part due to its base modification, thus revealing its great potency in binding but not catalysis. Under certain circumstances, 1664-TP can be slowly incorporated by RdRP through regular Watson-Crick base pairing, as evidenced by enzymology data and an HNC-1664-incorporated crystal structure of the RdRP-RNA complex. Overall, HNC-1664 achieves broad-spectrum characteristics by favoring an alternative base pairing strategy to non-catalytically block RNA synthesis, providing a novel concept for the rational development of NA drugs.
History
DepositionJan 4, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Genome polyprotein
B: RNA (35-MER)
C: RNA (17-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3124
Polymers70,2463
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4120 Å2
ΔGint-43 kcal/mol
Surface area24010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.976, 77.858, 154.621
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Genome polyprotein


Mass: 53408.461 Da / Num. of mol.: 1 / Mutation: C291M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterovirus A71 / Strain: SK-EV006-LPS1 / Variant: C291M / Production host: Escherichia coli (E. coli)
References: UniProt: E5RPG3, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#2: RNA chain RNA (35-MER)


Mass: 11370.859 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: RNA chain RNA (17-MER)


Mass: 5467.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.69 Å3/Da / Density % sol: 54.31 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: PEG 5000, ammonium sulfate, glycerol, MES, HEPES, sodium chloride, magnesium chloride, TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Apr 30, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 3→35.5 Å / Num. obs: 15781 / % possible obs: 99.8 % / Redundancy: 5.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.099 / Rrim(I) all: 0.121 / Net I/σ(I): 15.1
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
3-3.080.48721060.8330.5941
3.08-3.160.38621180.9070.4691
3.16-3.260.27620210.9550.3361
3.26-3.360.24120220.9590.2931
3.36-3.470.19719140.9670.241
3.47-3.590.17918460.9780.2171
3.59-3.720.13418010.9860.1621
3.72-3.880.10817210.9890.1321
3.88-4.050.09416300.9910.1151
4.05-4.250.07715870.9930.0931
4.25-4.480.0715240.9940.0861
4.48-4.750.06614340.9950.081
4.75-5.070.06713150.9960.0821
5.07-5.480.06112420.9950.0741
5.48-60.06111480.9950.0741
6-6.710.0610340.9950.0731
6.71-7.750.0459200.9970.0551
7.75-9.490.037670.9990.0361
9.49-13.430.0216020.9990.0261
13.43-35.50.0193060.9990.0241

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F8G

5f8g


Resolution: 3→35.5 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2909 780 4.96 %
Rwork0.2356 --
obs0.2384 15732 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→35.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3487 793 1 0 4281
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.177
X-RAY DIFFRACTIONf_dihedral_angle_d10.397924
X-RAY DIFFRACTIONf_chiral_restr0.059737
X-RAY DIFFRACTIONf_plane_restr0.009669
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.190.36051180.3022422X-RAY DIFFRACTION99
3.19-3.440.3241410.26642433X-RAY DIFFRACTION100
3.44-3.780.28261260.23342464X-RAY DIFFRACTION100
3.78-4.330.27171340.19712489X-RAY DIFFRACTION100
4.33-5.450.25151270.21282506X-RAY DIFFRACTION100
5.45-35.50.30311340.25072638X-RAY DIFFRACTION100

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