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Basic information

Entry
Database: PDB / ID: 4ovz
TitleX-Ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-Like Proteases
Components(Papain-like proteinase) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / CoV / coronavirus / HCoV / human coronavirus / SARS / severe acute respiratory syndrome / MERS / Middle East respiratory syndrome / PLpro / 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 / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / 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 / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / 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 / 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 / methylation / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / 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 / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / 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 / RNA-directed RNA polymerase activity / proteolysis / zinc ion binding / identical protein binding / membrane
Similarity search - Function
Papain-like viral protease, N-terminal domain / Papain-like viral protease, thumb domain / Jelly Rolls - #1680 / 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 / Papain-like viral protease, thumb domain / Jelly Rolls - #1680 / 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 / 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 / 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 / Jelly Rolls / Roll / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Sandwich / Orthogonal Bundle / Mainly Beta
Similarity search - Domain/homology
Chem-P85 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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: Database references
Revision 1.2Feb 4, 2015Group: Derived calculations
Revision 1.3Nov 22, 2017Group: Advisory / Derived calculations ...Advisory / Derived calculations / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_struct_oper_list ...entity_src_gen / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_residues / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _software.name
Revision 1.4Sep 27, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_residues / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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 proteinase
B: Papain-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,47812
Polymers71,1532
Non-polymers1,32510
Water1,35175
1
A: Papain-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1184
Polymers35,5841
Non-polymers5343
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Papain-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3608
Polymers35,5681
Non-polymers7917
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)119.772, 73.508, 98.269
Angle α, β, γ (deg.)90.000, 103.660, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Papain-like proteinase / non-structural protein 3 / nsp3 / PL2-PRO / PL-PRO / SARS coronavirus main proteinase


Mass: 35584.270 Da / Num. of mol.: 1
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
#2: Protein Papain-like proteinase / non-structural protein 3 / nsp3 / PL2-PRO / PL-PRO / SARS coronavirus main proteinase


Mass: 35568.270 Da / Num. of mol.: 1
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, 85 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-P85 / N-[(4-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
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 3.03 Å3/Da / Density % sol: 59.45 %
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 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.5→100 Å / Num. all: 24909 / Num. obs: 24909 / % possible obs: 99.8 % / Redundancy: 4.2 % / Biso Wilson estimate: 30.87 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 19.3
Reflection shell% possible obs: 100 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.696 / Mean I/σ(I) obs: 1.8

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Processing

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

3mj5


Resolution: 2.5→35.746 Å / FOM work R set: 0.8156 / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2429 1265 5.08 %
Rwork0.1821 23644 -
obs0.1852 24909 85.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 200.1 Å2 / Biso mean: 36.65 Å2 / Biso min: 8.84 Å2
Refinement stepCycle: final / Resolution: 2.5→35.746 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4395 0 138 73 4606
Biso mean--29.21 28.48 -
Num. residues----557
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0264580
X-RAY DIFFRACTIONf_angle_d1.7356209
X-RAY DIFFRACTIONf_chiral_restr0.124686
X-RAY DIFFRACTIONf_plane_restr0.008779
X-RAY DIFFRACTIONf_dihedral_angle_d18.5811631
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5-2.59620.2354500.162386691629
2.5962-2.71430.2596810.16881619170053
2.7143-2.85730.26881550.18352762291792
2.8573-3.03620.26561570.185130363193100
3.0362-3.27050.22741550.178430553210100
3.2705-3.59940.20541460.167630743220100
3.5994-4.11960.20511750.16430613236100
4.1196-5.18770.24041670.171930553222100
5.1877-35.74990.29661790.22533116329599

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