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- PDB-7qcg: Structure of SARS-CoV-2 Papain-like Protease bound to N-(2-pyrrol... -

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Basic information

Entry
Database: PDB / ID: 7qcg
TitleStructure of SARS-CoV-2 Papain-like Protease bound to N-(2-pyrrolidyl)-3,4,5-trihydroxybenzoylhydrazone
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 single-stranded poly(A) binding domain ...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 single-stranded poly(A) binding domain / 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 / NSP1, C-terminal domain, betacoronavirus / Betacoronavirus replicase NSP1 / 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
Chem-DZI / PHOSPHATE ION / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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 support4items
OrganizationGrant numberCountry
Helmholtz AssociationFISCOV
Helmholtz AssociationSFragX
German Federal Ministry for Education and Research16GW0277
German Federal Ministry for Education and Research031B0405D
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 23, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 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
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 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)36,61410
Polymers35,6881
Non-polymers9269
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint-30 kcal/mol
Surface area15590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.208, 83.208, 134.033
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, 267 molecules

#2: Chemical ChemComp-DZI / 3,4,5-tris(oxidanyl)-N-[(E)-1H-pyrrol-2-ylmethylideneamino]benzamide / N-(2-pyrrolidyl)-3,4,5-trihydroxybenzoylhydrazone


Mass: 261.233 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H11N3O4 / 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / 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: 1.75→63.47 Å / Num. obs: 54829 / % possible obs: 99.96 % / Redundancy: 10.5 % / Biso Wilson estimate: 33.63 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.39
Reflection shellResolution: 1.75→1.813 Å / Num. unique obs: 5449 / CC1/2: 0.545

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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: 1.75→63.47 Å / SU ML: 0.2064 / Cross valid method: FREE R-VALUE / σ(F): 1.44 / Phase error: 22.1953
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1983 2742 5 %
Rwork0.1896 52087 -
obs0.1901 54829 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.3 Å2
Refinement stepCycle: LAST / Resolution: 1.75→63.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2499 0 53 258 2810
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072683
X-RAY DIFFRACTIONf_angle_d0.85393653
X-RAY DIFFRACTIONf_chiral_restr0.0509396
X-RAY DIFFRACTIONf_plane_restr0.0066467
X-RAY DIFFRACTIONf_dihedral_angle_d23.0122971
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.780.36171090.31032582X-RAY DIFFRACTION99.04
1.78-1.810.30111580.29412584X-RAY DIFFRACTION100
1.81-1.850.30921190.28012555X-RAY DIFFRACTION100
1.85-1.880.26581470.27712550X-RAY DIFFRACTION100
1.88-1.930.2421500.25712604X-RAY DIFFRACTION100
1.93-1.970.27461360.24682547X-RAY DIFFRACTION100
1.97-2.020.25091340.23072568X-RAY DIFFRACTION100
2.02-2.070.2381530.21442580X-RAY DIFFRACTION99.96
2.07-2.140.23321340.21672579X-RAY DIFFRACTION100
2.14-2.20.20311170.20632591X-RAY DIFFRACTION100
2.2-2.280.2181150.20482608X-RAY DIFFRACTION99.89
2.28-2.370.21431340.20732608X-RAY DIFFRACTION99.96
2.37-2.480.21321270.20832592X-RAY DIFFRACTION99.96
2.48-2.610.24041270.20532600X-RAY DIFFRACTION100
2.61-2.780.26161450.20822636X-RAY DIFFRACTION100
2.78-2.990.22331540.20572581X-RAY DIFFRACTION100
2.99-3.290.18851540.1922606X-RAY DIFFRACTION100
3.29-3.770.15771530.16612641X-RAY DIFFRACTION100
3.77-4.750.1481410.14472667X-RAY DIFFRACTION100
4.75-63.470.1851350.17492808X-RAY DIFFRACTION99.73
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)
16.84544130235-1.24628623329-2.714591948714.916922494270.1960364573488.191002733760.228658858197-0.198506180970.6173246582120.07914320436260.01185352262310.371800677179-0.682662137645-0.423800321877-0.2285284112520.2612364049420.03030733630980.01290282009910.22910633289-0.0191662371220.28222072364139.519570088636.5984246937-5.20845725239
21.325928894030.260525729390.781047760231.253121007830.6262967178966.31376824401-0.0178684869941-0.02344592491840.0970440380753-0.0342248078927-0.02942547099990.0782117175963-0.17983014415-0.1302383254930.03744021945570.1933946798250.01165256516930.001111925561980.1908326679510.008618255464040.25088974243751.46353981229.0298841279-25.160681246
35.17038403158-0.9898738246880.4722190134454.2698663044-0.987632022542.64542194537-0.04558098113450.766462222265-0.0611844868501-0.401908645036-0.242585189571-0.8079772683720.3366963571271.093695884440.2657659537840.340796060150.07620849852050.09152404140720.5841824895590.01330516362430.40234125453273.843174375221.6752421872-39.8192859703
47.98810847936-1.83680801851.745170384442.44650603073-0.3182383783073.30503441501-0.03722581851230.681504591652-0.0256765188658-0.370008815280.029584064301-0.1011499426860.0565784694090.4743773123880.009474811001680.2956989632930.00204419900240.02181853817760.329123187443-0.01642488550760.16958184134957.181005447124.8211182755-44.6443925171
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 - 61
22chain 'A' and (resid 62 through 175 )62 - 17562 - 180
33chain 'A' and (resid 176 through 259 )176 - 259181 - 264
44chain 'A' and (resid 260 through 314 )260 - 314265 - 322

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