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- PDB-8aeb: SARS-CoV-2 Main Protease complexed with N-(pyridin-3-ylmethyl)thi... -

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Basic information

Entry
Database: PDB / ID: 8aeb
TitleSARS-CoV-2 Main Protease complexed with N-(pyridin-3-ylmethyl)thioformamide
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / 3C-like proteinase / cysteine protease / complex / inhibitor
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / snRNP Assembly / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / mRNA (guanine-N7)-methyltransferase / host cell Golgi apparatus / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / forked DNA-dependent helicase activity / single-stranded 3'-5' DNA helicase activity / four-way junction helicase activity / double-stranded DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / 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 / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / NSP1, C-terminal domain, betacoronavirus / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / : / : / Coronavirus replicase NSP7
Similarity search - Domain/homology
N-(pyridin-3-ylmethyl)thioformamide / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsHanoulle, X. / Charton, J. / Deprez, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses.
Authors: Brier, L. / Hassan, H. / Hanoulle, X. / Landry, V. / Moschidi, D. / Desmarets, L. / Rouille, Y. / Dumont, J. / Herledan, A. / Warenghem, S. / Piveteau, C. / Carre, P. / Ikherbane, S. / ...Authors: Brier, L. / Hassan, H. / Hanoulle, X. / Landry, V. / Moschidi, D. / Desmarets, L. / Rouille, Y. / Dumont, J. / Herledan, A. / Warenghem, S. / Piveteau, C. / Carre, P. / Ikherbane, S. / Cantrelle, F.X. / Dupre, E. / Dubuisson, J. / Belouzard, S. / Leroux, F. / Deprez, B. / Charton, J.
History
DepositionJul 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 15, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2268
Polymers33,8261
Non-polymers4007
Water2,306128
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,45216
Polymers67,6512
Non-polymers80114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area4890 Å2
ΔGint-78 kcal/mol
Surface area24960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.141, 53.472, 44.650
Angle α, β, γ (deg.)90.000, 101.304, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-604-

HOH

21A-612-

HOH

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Components

#1: Protein 3C-like proteinase nsp5 / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33825.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-35J / N-(pyridin-3-ylmethyl)thioformamide


Mass: 152.217 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.99 Å3/Da / Density % sol: 38.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2M NaFormate, 21% PEG 3350, 10% Glycerol, 8% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.980104 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.980104 Å / Relative weight: 1
ReflectionResolution: 1.83→48.373 Å / Num. obs: 23313 / % possible obs: 98.7 % / Redundancy: 6.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.093 / Rpim(I) all: 0.06 / Rrim(I) all: 0.111 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
8.18-48.456.40.0436.32940.9990.0250.04799.6
1.83-1.8861.221.215870.4760.81.46489.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
REFMAC5.8.0352refinement
XDSdata reduction
Aimless0.7.8data scaling
MOLREP11.9.02phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7K3T

7k3t


Resolution: 1.83→48.373 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.941 / SU B: 5.261 / SU ML: 0.143 / Cross valid method: FREE R-VALUE / ESU R: 0.159 / ESU R Free: 0.149
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2341 1170 5.098 %
Rwork0.1835 21779 -
all0.186 --
obs-22949 97.11 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 31.676 Å2
Baniso -1Baniso -2Baniso -3
1-1.247 Å20 Å20.718 Å2
2---0.583 Å2-0 Å2
3----0.88 Å2
Refinement stepCycle: LAST / Resolution: 1.83→48.373 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2341 0 22 128 2491
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0112425
X-RAY DIFFRACTIONr_bond_other_d0.0020.0162164
X-RAY DIFFRACTIONr_angle_refined_deg2.0671.6343295
X-RAY DIFFRACTIONr_angle_other_deg0.7141.5485038
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.395308
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.9549.54511
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.40810385
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.30310107
X-RAY DIFFRACTIONr_chiral_restr0.0990.2374
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.022776
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02487
X-RAY DIFFRACTIONr_nbd_refined0.2530.2460
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2150.22103
X-RAY DIFFRACTIONr_nbtor_refined0.1860.21199
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.090.21270
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1940.2117
X-RAY DIFFRACTIONr_metal_ion_refined0.3670.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1820.240
X-RAY DIFFRACTIONr_nbd_other0.1720.2103
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2490.219
X-RAY DIFFRACTIONr_mcbond_it3.9633.1911226
X-RAY DIFFRACTIONr_mcbond_other3.9633.191226
X-RAY DIFFRACTIONr_mcangle_it4.7344.7691533
X-RAY DIFFRACTIONr_mcangle_other4.7364.7731534
X-RAY DIFFRACTIONr_scbond_it5.2953.5861199
X-RAY DIFFRACTIONr_scbond_other5.33.5871200
X-RAY DIFFRACTIONr_scangle_it7.0285.1841761
X-RAY DIFFRACTIONr_scangle_other7.0265.1861762
X-RAY DIFFRACTIONr_lrange_it8.80647.812682
X-RAY DIFFRACTIONr_lrange_other8.76547.0432661
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.83-1.8780.408710.39215160.39317250.8460.746920.331
1.878-1.9290.364860.36115260.36117060.8630.79994.490.314
1.929-1.9850.308810.31714870.31716550.8770.86594.74320.277
1.985-2.0460.316800.29714420.29815930.8970.88695.5430.25
2.046-2.1130.304740.24713890.2515420.9070.93894.87680.216
2.113-2.1870.277660.21513610.21814980.9410.95895.26030.188
2.187-2.2690.249770.19513120.19814410.9620.97296.39140.173
2.269-2.3620.234670.18413010.18714110.9630.97796.95250.167
2.362-2.4660.288700.16912300.17513250.9490.98298.11320.152
2.466-2.5860.21500.16111870.16312530.9770.98498.72310.152
2.586-2.7260.339630.1911690.19612360.9470.97899.67640.179
2.726-2.8910.258610.17811080.18311710.960.9899.82920.171
2.891-3.0890.19660.1769990.17710650.9750.9811000.175
3.089-3.3360.188510.1689820.16910330.9740.9831000.17
3.336-3.6520.203530.1738740.1759270.9770.9831000.18
3.652-4.0810.212400.1458110.1488510.9780.9881000.159
4.081-4.7060.173380.1177170.1197550.9810.9921000.136
4.706-5.750.196360.1256110.1296470.9810.9921000.142
5.75-8.0760.2300.1414640.1454940.980.9891000.159
8.076-48.3730.181100.1552930.1563030.9730.9851000.18

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