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- PDB-7qci: Structure of SARS-CoV-2 Papain-like Protease bound to N-(3,4-dihy... -

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Basic information

Entry
Database: PDB / ID: 7qci
TitleStructure of SARS-CoV-2 Papain-like Protease bound to N-(3,4-dihydroxybenzylidene)-thiosemicarbazone
ComponentsPapain-like protease nsp3
KeywordsHYDROLASE / Cystein-Protease / Inhibitor / SARS-CoV-2 / Hydrazone / Deubiquitination
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / endonuclease 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 cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
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 / Betacoronavirus Nsp3c-M 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / Coronavirus 3Ecto domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
N-(3,4-dihydroxybenzylidene)-thiosemicarbazone / PHOSPHATE ION / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 Å
AuthorsEwert, W. / Gunther, S. / Reinke, P. / Falke, S. / Lieske, J. / Miglioli, F. / Carcelli, M. / Srinivasan, V. / Betzel, C. / Han, H. ...Ewert, W. / Gunther, S. / Reinke, P. / Falke, S. / Lieske, J. / Miglioli, F. / Carcelli, M. / Srinivasan, V. / Betzel, C. / Han, H. / Lorenzen, K. / Guenther, C. / Niebling, S. / Garcia-Alai, M. / Hinrichs, W. / Rogolino, D. / Meents, A.
Funding support Germany, 4items
OrganizationGrant numberCountry
Helmholtz AssociationFISCOV Germany
Helmholtz AssociationSFragX Germany
German Federal Ministry for Education and Research16GW0277 Germany
German Federal Ministry for Education and Research031B0405D Germany
CitationJournal: Front Chem / Year: 2022
Title: Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease.
Authors: Ewert, W. / Gunther, S. / Miglioli, F. / Falke, S. / Reinke, P.Y.A. / Niebling, S. / Gunther, C. / Han, H. / Srinivasan, V. / Brognaro, H. / Lieske, J. / Lorenzen, K. / Garcia-Alai, M.M. / ...Authors: Ewert, W. / Gunther, S. / Miglioli, F. / Falke, S. / Reinke, P.Y.A. / Niebling, S. / Gunther, C. / Han, H. / Srinivasan, V. / Brognaro, H. / Lieske, J. / Lorenzen, K. / Garcia-Alai, M.M. / Betzel, C. / Carcelli, M. / Hinrichs, W. / Rogolino, D. / Meents, A.
History
DepositionNov 24, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: 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_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 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: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,68711
Polymers35,6881
Non-polymers99910
Water5,116284
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-32 kcal/mol
Surface area15380 Å2
Unit cell
Length a, b, c (Å)83.366, 83.366, 133.887
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Papain-like protease nsp3 / Non-structural protein 3 / nsp3 / PL2-PRO / Papain-like proteinase / PL-PRO


Mass: 35687.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTC1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases

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Non-polymers , 6 types, 294 molecules

#2: Chemical ChemComp-A6Q / N-(3,4-dihydroxybenzylidene)-thiosemicarbazone / 1-[(E)-[3,4-bis(oxidanyl)phenyl]methylideneamino]-3-ethyl-thiourea


Mass: 239.294 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N3O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 284 / Source method: isolated from a natural source / Formula: H2O

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Details

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

Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Tris-HCl pH 8.0, 10% glycerol, 0.8 M sodium dihydrogenphosphate, 1.2 M potassium hydrogenphosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.76→39.8 Å / Num. obs: 54008 / % possible obs: 99.91 % / Redundancy: 10.6 % / Biso Wilson estimate: 33.02 Å2 / CC1/2: 0.999 / Net I/σ(I): 13.32
Reflection shellResolution: 1.76→1.823 Å / Num. unique obs: 5301 / CC1/2: 0.517

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Processing

Software
NameVersionClassification
PHENIX1.18-3855_9999refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7nfv

7nfv


Resolution: 1.76→39.8 Å / SU ML: 0.2187 / Cross valid method: FREE R-VALUE / σ(F): 1.42 / Phase error: 25.9867
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2145 2651 4.91 %
Rwork0.1918 51355 -
obs0.1929 54006 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.39 Å2
Refinement stepCycle: LAST / Resolution: 1.76→39.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2499 0 55 284 2838
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01322663
X-RAY DIFFRACTIONf_angle_d1.12793624
X-RAY DIFFRACTIONf_chiral_restr0.0691394
X-RAY DIFFRACTIONf_plane_restr0.0103460
X-RAY DIFFRACTIONf_dihedral_angle_d14.8256368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.76-1.790.3641210.3782659X-RAY DIFFRACTION99.68
1.79-1.830.35781140.35772673X-RAY DIFFRACTION99.96
1.83-1.860.32991300.31582664X-RAY DIFFRACTION99.96
1.86-1.90.32951260.30172703X-RAY DIFFRACTION99.96
1.9-1.950.30921490.28282673X-RAY DIFFRACTION99.93
1.95-20.27131310.26322681X-RAY DIFFRACTION99.96
2-2.050.25371320.24022654X-RAY DIFFRACTION99.79
2.05-2.110.24791280.23062688X-RAY DIFFRACTION99.93
2.11-2.180.24991470.21492689X-RAY DIFFRACTION99.96
2.18-2.260.2181510.20432692X-RAY DIFFRACTION99.82
2.26-2.350.2321630.20152641X-RAY DIFFRACTION99.82
2.35-2.450.19991520.20052700X-RAY DIFFRACTION99.93
2.45-2.580.24121170.20672716X-RAY DIFFRACTION100
2.58-2.750.24661370.20682691X-RAY DIFFRACTION100
2.75-2.960.2961440.2082710X-RAY DIFFRACTION100
2.96-3.260.22351490.19352716X-RAY DIFFRACTION99.97
3.26-3.730.20171450.16352738X-RAY DIFFRACTION100
3.73-4.690.14391660.14112773X-RAY DIFFRACTION100
4.7-39.80.19441490.17492894X-RAY DIFFRACTION99.77
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.22497706614-1.67881695078-2.973385487094.421492519110.5815839573948.653551796180.206939793983-0.2577069728170.6883858387520.1044114533860.05919500122310.268149577001-0.693747132223-0.383700470932-0.2595702372360.2928855456180.02427283006780.01865311081710.244747362992-0.02205306368890.27939474712339.578041958436.6675986188-5.26025362429
22.382965080340.3509032852951.493405039021.975389672851.075994913779.46849993958-0.0090841899078-0.02574067815950.11155030073-0.0781273578201-0.03107035294540.0268981818653-0.185741634116-0.0963488715290.02286663346710.1791873738770.004578163278730.01832790493750.1749682053160.01728395987510.21488822710151.75238389728.9449612515-24.9731098549
35.29572358617-0.2202237958820.06676822157533.73348917884-1.029287529043.47793939055-0.1076053766790.7149465562160.0310021499425-0.406016323094-0.251942468251-0.7980310256160.1437907843061.06840927620.3348120358870.3588672717230.04149932848310.0759232850470.5994841781060.04388830272880.38336733766771.993629789623.714949848-39.9946374993
48.59971320833-1.054851017741.107888770611.626459078130.1796475619492.80990175018-0.01340449656130.876888816263-0.492743089813-0.3216005707140.0315097551645-0.07139051136660.312398082020.3795332564150.009367432249090.3408856286990.02601136461120.02335599107380.335912113681-0.04125449893590.21868456582957.16160148121.9701787282-44.8930684152
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 2 through 61 )2 - 612 - 62
22chain 'A' and (resid 62 through 175 )62 - 17563 - 177
33chain 'A' and (resid 176 through 270 )176 - 270178 - 274
44chain 'A' and (resid 271 through 314 )271 - 314275 - 321

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