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- EMDB-30572: Structure of COVID-19 RNA-dependent RNA polymerase bound to suramin -

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Basic information

Entry
Database: EMDB / ID: EMD-30572
TitleStructure of COVID-19 RNA-dependent RNA polymerase bound to suramin
Map data
SampleCOVID-19 RdRp complex bound to suramin
  • (Non-structural protein ...Viral nonstructural protein) x 2
  • RNA-directed RNA polymeraseRNA-dependent RNA polymerase
  • (ligand) x 2
Function / homology
Function and homology information


Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / exoribonuclease activity / RNA phosphodiester bond hydrolysis, exonucleolytic / modulation by virus of host autophagy / mRNA methylation ...Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / exoribonuclease activity / RNA phosphodiester bond hydrolysis, exonucleolytic / modulation by virus of host autophagy / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific protease activity / host cell Golgi apparatus / Replication of the SARS-CoV-2 genome / suppression by virus of host type I interferon production / host cell endoplasmic reticulum / induction by virus of catabolism of host mRNA / SARS coronavirus main proteinase / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / G-quadruplex RNA binding / 3'-5'-exoribonuclease activity / suppression by virus of host ISG15-protein conjugation / host cell endoplasmic reticulum-Golgi intermediate compartment / protein K48-linked deubiquitination / suppression by virus of host toll-like receptor signaling pathway / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / transcription, RNA-templated / suppression by virus of host NF-kappaB cascade / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / positive stranded viral RNA replication / protein autoprocessing / cysteine-type peptidase activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / viral genome replication / suppression by virus of host TRAF activity / helicase activity / viral transcription / Transferases; Transferring one-carbon groups; Methyltransferases / ubiquitinyl hydrolase 1 / methyltransferase activity / DNA helicase / thiol-dependent deubiquitinase / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / DNA helicase activity / single-stranded RNA binding / host cell perinuclear region of cytoplasm / methylation / RNA helicase / induction by virus of host autophagy / endonuclease activity / RNA-directed RNA polymerase / RNA helicase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / viral protein processing / suppression by virus of host type I interferon-mediated signaling pathway / Hydrolases; Acting on ester bonds / transcription, DNA-templated / host cell cytoplasm / protein dimerization activity / protein homodimerization activity / zinc ion binding / integral component of membrane / ATP binding / identical protein binding / cytosol
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nonstructural protein 14, betacoronavirus / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Viral (Superfamily 1) RNA helicase / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Non-structural protein 14, coronavirus / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP16, coronavirus-like / Coronavirus proofreading exoribonuclease / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, middle domain superfamily / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP15, middle domain / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein 2, SARS-CoV-like / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / Endoribonuclease EndoU-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Betacoronavirus Nsp3c-M domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus replicase NSP1 / Non-structural protein NSP1, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Coronavirus (CoV) Nsp1 globular domain profile. / Non-structural protein 6, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Lipocalin signature. / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Coronavirus replicase NSP7 / Coronavirus papain-like peptidase / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus RNA synthesis protein NSP10 / Coronavirus endopeptidase C30 / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP8 / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Coronavirus replicase NSP4, N-terminal / RNA synthesis protein NSP10, coronavirus / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Coronavirus replicase NSP4, N-terminal / Peptidase C30, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein 6, coronavirus / Peptidase C30, domain 3, coronavirus
Similarity search - Domain/homology
Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.57 Å
AuthorsLi Z / Yin W / Zhou Z / Yu X / Xu H
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin.
Authors: Wanchao Yin / Xiaodong Luan / Zhihai Li / Ziwei Zhou / Qingxing Wang / Minqi Gao / Xiaoxi Wang / Fulai Zhou / Jingjing Shi / Erli You / Mingliang Liu / Qingxia Wang / Yi Jiang / Hualiang ...Authors: Wanchao Yin / Xiaodong Luan / Zhihai Li / Ziwei Zhou / Qingxing Wang / Minqi Gao / Xiaoxi Wang / Fulai Zhou / Jingjing Shi / Erli You / Mingliang Liu / Qingxia Wang / Yi Jiang / Hualiang Jiang / Gengfu Xiao / Leike Zhang / Xuekui Yu / Shuyang Zhang / H Eric Xu /
Abstract: The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS- ...The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
History
DepositionSep 23, 2020-
Header (metadata) releaseNov 11, 2020-
Map releaseNov 11, 2020-
UpdateMar 24, 2021-
Current statusMar 24, 2021Processing site: PDBj / Status: Released

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Structure visualization

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  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.03
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  • Surface view with fitted model
  • Atomic models: PDB-7d4f
  • Surface level: 0.03
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30572.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.664 Å
1.07 Å/pix.
x 256 pix.
= 273.664 Å
1.07 Å/pix.
x 256 pix.
= 273.664 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.069 Å
Density
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.10618801 - 0.20450965
Average (Standard dev.)2.5831025e-06 (±0.006527724)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.664 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0691.0691.069
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z273.664273.664273.664
α/β/γ90.00090.00090.000
start NX/NY/NZ1219875
NX/NY/NZ141223232
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.1060.2050.000

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Supplemental data

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Sample components

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Entire COVID-19 RdRp complex bound to suramin

EntireName: COVID-19 RdRp complex bound to suramin / Number of Components: 6

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Component #1: protein, COVID-19 RdRp complex bound to suramin

ProteinName: COVID-19 RdRp complex bound to suramin / Recombinant expression: No
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #2: protein, Non-structural protein 8

ProteinName: Non-structural protein 8 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 22.034242 kDa
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, Non-structural protein 7

ProteinName: Non-structural protein 7 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 9.38 kDa
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, RNA-directed RNA polymerase

ProteinName: RNA-directed RNA polymeraseRNA-dependent RNA polymerase
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 107.96525 kDa
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #5: ligand, ZINC ION

LigandName: ZINC ION / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 6.540905 MDa

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Component #6: ligand, 8-(3-(3-aminobenzamido)-4-methylbenzamido)naphthalene-1,3...

LigandName: 8-(3-(3-aminobenzamido)-4-methylbenzamido)naphthalene-1,3,5-trisulfonic acid
Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.635643 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionpH: 7.4
VitrificationCryogen Name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 68 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of Projections: 95845
3D reconstructionResolution: 2.57 Å / Resolution Method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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