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- PDB-8uob: SARS-CoV-2 Papain-like protease (PLpro) with Inhibitor Jun12682 -

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Basic information

Entry
Database: PDB / ID: 8uob
TitleSARS-CoV-2 Papain-like protease (PLpro) with Inhibitor Jun12682
ComponentsPapain-like protease nsp3
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / Inhibitor / Noncovalent / Papain-like protease / SARS-COV-2 / VIRAL PROTEIN-INHIBITOR complex / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / endonuclease activity / 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 ...viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / endonuclease activity / 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 / methylation / SARS coronavirus main proteinase / 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 / 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 / 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 / symbiont-mediated activation of host autophagy / viral translational frameshifting / 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
Coronavirus replicase NSP2, C-terminal / 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 ...Coronavirus replicase NSP2, C-terminal / 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 / Betacoronavirus replicase NSP1 / 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 (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 Nsp3 ectodomain (3Ecto) 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
: / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsAnsari, A. / Tan, B. / Ruiz, F.X. / Wang, J. / Arnold, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Science / Year: 2024
Title: Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.
Authors: Tan, B. / Zhang, X. / Ansari, A. / Jadhav, P. / Tan, H. / Li, K. / Chopra, A. / Ford, A. / Chi, X. / Ruiz, F.X. / Arnold, E. / Deng, X. / Wang, J.
History
DepositionOct 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,90810
Polymers35,9441
Non-polymers9649
Water3,639202
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)115.825, 115.825, 219.317
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number98
Space group name H-MI4122
Space group name HallI4bw2bw
Symmetry operation#1: x,y,z
#2: -y+1/2,x,z+3/4
#3: y+1/2,-x,z+3/4
#4: x+1/2,-y,-z+3/4
#5: -x+1/2,y,-z+3/4
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
#9: x+1/2,y+1/2,z+1/2
#10: -y+1,x+1/2,z+5/4
#11: y+1,-x+1/2,z+5/4
#12: x+1,-y+1/2,-z+5/4
#13: -x+1,y+1/2,-z+5/4
#14: -x+1/2,-y+1/2,z+1/2
#15: y+1/2,x+1/2,-z+1/2
#16: -y+1/2,-x+1/2,-z+1/2

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Components

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


Mass: 35943.762 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-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P0DTC1, ubiquitinyl hydrolase 1
#2: Chemical ChemComp-XB5 / 5-[2-(dimethylamino)ethoxy]-N-{(1R)-1-[(3M,5P)-3-(1-ethyl-1H-pyrazol-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-2-methylbenzamide


Mass: 500.635 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H36N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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 / pH: 6.2 / Details: Zinc Acetate, PEG 8000, Bis-Tris 6.3 / PH range: 5.5-6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Sep 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.52→34.74 Å / Num. obs: 25626 / % possible obs: 100 % / Redundancy: 15.2 % / Biso Wilson estimate: 59.55 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.304 / Rrim(I) all: 0.315 / Net I/σ(I): 7.61
Reflection shellResolution: 2.52→2.61 Å / Num. unique obs: 2834 / CC1/2: 0.4

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROC1.20.1_4487data processing
autoPROCdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.52→34.74 Å / SU ML: 0.4086 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0756
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2445 1309 5.12 %
Rwork0.2063 24267 -
obs0.2083 25576 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.32 Å2
Refinement stepCycle: LAST / Resolution: 2.52→34.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2454 0 45 202 2701
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00182562
X-RAY DIFFRACTIONf_angle_d0.44613483
X-RAY DIFFRACTIONf_chiral_restr0.0374383
X-RAY DIFFRACTIONf_plane_restr0.0042455
X-RAY DIFFRACTIONf_dihedral_angle_d12.0999942
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.52-2.620.38921260.36442627X-RAY DIFFRACTION99.24
2.62-2.740.34511630.31982660X-RAY DIFFRACTION99.89
2.74-2.880.30291500.30852645X-RAY DIFFRACTION99.89
2.88-3.070.32671370.26612663X-RAY DIFFRACTION99.96
3.07-3.30.24551350.23382673X-RAY DIFFRACTION99.93
3.3-3.630.25121440.20732690X-RAY DIFFRACTION100
3.63-4.160.20371430.17832709X-RAY DIFFRACTION100
4.16-5.240.20431650.16372724X-RAY DIFFRACTION100
5.24-34.740.23921460.18192876X-RAY DIFFRACTION99.93

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