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- PDB-8uvm: SARS-CoV-2 papain-like protease (PLpro) complex with covalent inh... -

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Entry
Database: PDB / ID: 8uvm
TitleSARS-CoV-2 papain-like protease (PLpro) complex with covalent inhibitor Jun11313
ComponentsPapain-like protease nsp3
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / SARS CoV-2 Papain Like protease complex / Covalent inhibitor / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / mRNA guanylyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / mRNA guanylyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / symbiont-mediated suppression of host toll-like receptor signaling pathway / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / copper ion binding / symbiont-mediated suppression of host gene expression / symbiont-mediated activation of host autophagy / viral translational frameshifting / 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
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / 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. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / 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 / 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.
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsAnsari, A. / Tan, B. / Chopra, A. / Ruiz, F.X. / Arnold, E. / Wang, J.
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
DepositionNov 3, 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
Revision 1.2Oct 23, 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

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Assembly

Deposited unit
A: Papain-like protease nsp3
B: Papain-like protease nsp3
C: Papain-like protease nsp3
D: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,68521
Polymers143,7754
Non-polymers2,91017
Water3,333185
1
A: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6625
Polymers35,9441
Non-polymers7194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6625
Polymers35,9441
Non-polymers7194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6625
Polymers35,9441
Non-polymers7194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6986
Polymers35,9441
Non-polymers7545
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)190.997, 190.997, 112.926
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number150
Space group name H-MP321
Space group name HallP32"
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x-y,-y,-z
#5: -x,-x+y,-z
#6: y,x,-z

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 35943.762 Da / Num. of mol.: 4
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 (E. coli)
References: UniProt: P0DTD1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases

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Non-polymers , 5 types, 202 molecules

#2: Chemical
ChemComp-Y3R / ethyl 4-oxo-4-(2-{3-[2-({(1S)-1-[(3P)-3-(thiophen-3-yl)phenyl]ethyl}carbamoyl)phenyl]propanoyl}hydrazinyl)butanoate


Mass: 521.628 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H31N3O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 185 / 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

CrystalDensity Matthews: 4.13 Å3/Da / Density % sol: 70.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 2.5M Ammonium Sulfate, 0.1M Sodium citrate dibasic trihydrate pH 6.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 29, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.85→42 Å / Num. obs: 55567 / % possible obs: 99.8 % / Redundancy: 18.9 % / Biso Wilson estimate: 59.44 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.187 / Rpim(I) all: 0.043 / Rrim(I) all: 0.193 / Net I/σ(I): 10.67
Reflection shellResolution: 2.85→2.9 Å / Redundancy: 8.9 % / Rmerge(I) obs: 0.944 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2673 / CC1/2: 0.472 / Rpim(I) all: 0.309 / Rrim(I) all: 0.998 / % possible all: 96.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→41.9 Å / Cross valid method: FREE R-VALUE / σ(F): 736.04 / Phase error: 27.0223
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2036 2823 5.17 %
Rwork0.1781 51828 -
obs0.1801 54651 98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.96 Å2
Refinement stepCycle: LAST / Resolution: 2.85→41.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9782 0 177 185 10144
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.001610193
X-RAY DIFFRACTIONf_angle_d0.379113861
X-RAY DIFFRACTIONf_chiral_restr0.03651534
X-RAY DIFFRACTIONf_plane_restr0.00281774
X-RAY DIFFRACTIONf_dihedral_angle_d14.87863589
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.90.26171290.23712135X-RAY DIFFRACTION77.22
2.9-2.950.32091090.23442472X-RAY DIFFRACTION90.28
2.95-3.010.27321390.23062508X-RAY DIFFRACTION91.13
3.01-3.070.28411480.23682533X-RAY DIFFRACTION91.35
3.07-3.130.25351590.2372558X-RAY DIFFRACTION92.45
3.13-3.210.28831540.22692577X-RAY DIFFRACTION93.2
3.21-3.290.21411260.22052601X-RAY DIFFRACTION94.62
3.29-3.380.24311530.21132616X-RAY DIFFRACTION94.07
3.38-3.470.24741610.19512605X-RAY DIFFRACTION93.57
3.47-3.590.23361310.19382612X-RAY DIFFRACTION94.81
3.59-3.710.23681440.18582631X-RAY DIFFRACTION94.64
3.72-3.860.20911270.17662633X-RAY DIFFRACTION95.05
3.86-4.040.21021280.16442671X-RAY DIFFRACTION95.19
4.04-4.250.15771490.1652607X-RAY DIFFRACTION94.32
4.25-4.520.18041320.15042677X-RAY DIFFRACTION95
4.52-4.870.1661290.14622656X-RAY DIFFRACTION95.3
4.87-5.350.19451320.15952661X-RAY DIFFRACTION95.24
5.36-6.130.20181430.1822687X-RAY DIFFRACTION94.78
6.13-7.710.17781500.18012678X-RAY DIFFRACTION94.4
7.72-41.90.14271500.14782740X-RAY DIFFRACTION92.98

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