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Basic information

Entry
Database: PDB / ID: 4ow0
TitleX-Ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-Like Proteases
Componentspapain-like protease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / CoV / coronavirus / HCoV / human coronavirus / SARS / severe acute respiratory syndrome / MERS / Middle East respiratory syndrome / PLpro / papain-like protease / inhibitor / complex / DUB / deubiquitinating enzyme / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication ...Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication / methyltransferase activity / SARS-CoV-1 activates/modulates innate immune responses / methylation / double membrane vesicle viral factory outer membrane / 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 / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / induction by virus of host autophagy / symbiont-mediated suppression of host gene expression / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / proteolysis / zinc ion binding / membrane / identical protein binding
Similarity search - Function
Papain-like viral protease, N-terminal domain / Jelly Rolls - #1680 / Papain-like viral protease, thumb domain / Non-structural protein 3, SUD-N macrodomain, SARS-CoV / Helicase, Ruva Protein; domain 3 / Ubiquitin-like (UB roll) / 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 ...Papain-like viral protease, N-terminal domain / Jelly Rolls - #1680 / Papain-like viral protease, thumb domain / Non-structural protein 3, SUD-N macrodomain, SARS-CoV / Helicase, Ruva Protein; domain 3 / Ubiquitin-like (UB roll) / 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 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Jelly Rolls / Peptidase S1, PA clan, chymotrypsin-like fold / Roll / Peptidase S1, PA clan / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-S88 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsBaez-Santos, Y.M. / Mesecar, A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases.
Authors: Baez-Santos, Y.M. / Barraza, S.J. / Wilson, M.W. / Agius, M.P. / Mielech, A.M. / Davis, N.M. / Baker, S.C. / Larsen, S.D. / Mesecar, A.D.
History
DepositionJan 28, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2014Group: Data collection / Database references
Revision 1.2Feb 4, 2015Group: Derived calculations
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine_hist / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: papain-like protease
B: papain-like protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,37510
Polymers71,1372
Non-polymers1,2388
Water3,315184
1
A: papain-like protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2736
Polymers35,5681
Non-polymers7045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: papain-like protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1024
Polymers35,5681
Non-polymers5343
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)119.421, 74.388, 98.328
Angle α, β, γ (deg.)90.000, 104.110, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein papain-like protease / / NON-STRUCTURAL PROTEIN 3 / NSP3 / PL2-PRO / PL-PRO / SARS CORONAVIRUS MAIN PROTEINASE


Mass: 35568.270 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS coronavirus / Strain: Urbani / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P0C6U8, ubiquitinyl hydrolase 1, SARS coronavirus main proteinase

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Non-polymers , 5 types, 192 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-S88 / N-[(3-fluorophenyl)methyl]-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide


Mass: 390.493 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H27FN2O
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 184 / Source method: isolated from a natural source / Formula: H2O

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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: 2.99 Å3/Da / Density % sol: 58.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 100 mM sodium citrate, pH 5.5, 40% (v/v) PEG 600

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→31.8 Å / Num. obs: 49274 / % possible obs: 98.6 % / Redundancy: 4.7 % / Biso Wilson estimate: 26.28 Å2 / Rmerge(I) obs: 0.062 / Net I/σ(I): 20.6
Reflection shellResolution: 2.1→2.14 Å / % possible obs: 96.1 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.523 / Mean I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PDB_EXTRACT3.14data extraction
PHENIX(phenix.refine: 1.8_1069)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MJ5

3mj5


Resolution: 2.1→31.787 Å / FOM work R set: 0.8523 / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2045 2134 5.06 %
Rwork0.176 40035 -
obs0.1775 42169 85.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 172.95 Å2 / Biso mean: 38.85 Å2 / Biso min: 13.89 Å2
Refinement stepCycle: final / Resolution: 2.1→31.787 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4511 0 104 184 4799
Biso mean--38.87 33.54 -
Num. residues----572
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0224697
X-RAY DIFFRACTIONf_angle_d1.4566370
X-RAY DIFFRACTIONf_chiral_restr0.078705
X-RAY DIFFRACTIONf_plane_restr0.007798
X-RAY DIFFRACTIONf_dihedral_angle_d17.0541708
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.14520.2586600.1612987104732
2.1452-2.19880.1824750.16061454152947
2.1988-2.25820.21950.16981901199661
2.2582-2.32470.2524970.17022244234173
2.3247-2.39970.2261290.17222697282687
2.3997-2.48540.23621570.17322988314597
2.4854-2.58490.22731730.17683059323299
2.5849-2.70250.23231670.17483058322599
2.7025-2.84490.20231750.1693042321799
2.8449-3.0230.21081920.17323055324799
3.023-3.25620.21351540.17783090324499
3.2562-3.58340.18711570.16783095325299
3.5834-4.1010.19661600.16433122328299
4.101-5.16330.16231840.16563091327599
5.1633-31.79040.23341590.21753152331198

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