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- PDB-7lfu: Crystal structure of the SARS CoV-1 Papain-like protease in compl... -

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Basic information

Entry
Database: PDB / ID: 7lfu
TitleCrystal structure of the SARS CoV-1 Papain-like protease in complex with peptide inhibitor VIR250
Components
  • Papain-like protease peptide inhibitor VIR250
  • papain-like protease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COVID-19 / CORONAVIRUS / SARS / COV-1 / COV-2 / PAPAIN-LIKE PROTEASE / PLPRO / DEUBIQUITINATING ENZYME / UBIQUITIN / ACTIVITY-BASED PROBE / 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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / 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 / viral protein processing / host cell perinuclear region of cytoplasm / 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
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / 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 ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Papain-like protease peptide inhibitor VIR250 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.29 Å
AuthorsOlsen, S.K. / Lv, Z.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM115568-06 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM128731-03 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RR200030 United States
CitationJournal: Cell Rep / Year: 2021
Title: A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.
Authors: Patchett, S. / Lv, Z. / Rut, W. / Bekes, M. / Drag, M. / Olsen, S.K. / Huang, T.T.
History
DepositionJan 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: papain-like protease
A: Papain-like protease peptide inhibitor VIR250


Theoretical massNumber of molelcules
Total (without water)37,1932
Polymers37,1932
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-7 kcal/mol
Surface area14550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.775, 90.408, 113.563
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein papain-like protease / pp1a / ORF1a polyprotein


Mass: 36688.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus
Gene: 1a / Plasmid: PET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL-21(DE3) RIL CODON PLUS
References: UniProt: P0C6U8, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, SARS coronavirus main proteinase
#2: Protein/peptide Papain-like protease peptide inhibitor VIR250


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 504.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: Papain-like protease peptide inhibitor VIR250
Compound detailsPeptide covalently linked to active site Cys
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

CrystalDensity Matthews: 2.44 Å3/Da / Density % sol: 49.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M sodium thiocyanate, and 20% w/v polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 108 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.29→70.731 Å / Num. obs: 16767 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 74.36 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.032 / Rrim(I) all: 0.081 / Net I/σ(I): 16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.29-2.375.82.147948616260.4080.9622.3590.7100
8.87-70.735.70.04818803320.9970.0220.0534699.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
PHASERphasing
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WUU

6wuu


Resolution: 2.29→70.731 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 33.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2647 1668 10.01 %
Rwork0.2244 14995 -
obs0.2285 16663 99.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 196.26 Å2 / Biso mean: 91.4347 Å2 / Biso min: 55.25 Å2
Refinement stepCycle: final / Resolution: 2.29→70.731 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2414 0 36 0 2450
Biso mean--84.22 --
Num. residues----306
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032507
X-RAY DIFFRACTIONf_angle_d0.4993398
X-RAY DIFFRACTIONf_chiral_restr0.037379
X-RAY DIFFRACTIONf_plane_restr0.003432
X-RAY DIFFRACTIONf_dihedral_angle_d14.8191466
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.29-2.35740.38021280.3603115893
2.3574-2.43350.36671380.35311239100
2.4335-2.52050.38291400.32081245100
2.5205-2.62140.38961360.32721229100
2.6214-2.74070.40331380.28931241100
2.7407-2.88520.35661370.28561232100
2.8852-3.0660.36391390.29011244100
3.066-3.30270.32571390.26991250100
3.3027-3.63510.33551400.25061259100
3.6351-4.1610.2291410.21591264100
4.161-5.24220.18981410.1731282100
5.2422-70.7310.2361510.19781352100
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)
15.3244-4.6022-1.37628.56630.60435.56850.3152-1.2036-0.31820.46110.12230.6517-0.6751-0.4089-0.34660.6749-0.07710.08070.87410.08330.674965.68232.995511.2804
26.22871.78943.11913.06611.6882.83410.1188-0.2849-0.047-0.0590.03230.43650.1408-0.3564-0.10320.65940.0860.02840.63290.19350.587788.970828.314615.5237
35.53691.7415-2.0585.94553.58514.0552-0.1525-0.397-1.44790.89420.111-0.63671.14840.20850.10520.99090.1522-0.05540.62020.1660.9104109.53917.726217.39
43.5671-0.4123-0.32637.77251.40842.89960.0119-0.2551-0.3130.12430.1314-0.90160.29510.3193-0.13310.53760.1009-0.02860.56040.06310.6427109.868226.820919.3916
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'D' and (resid 5 through 62 )D5 - 62
2X-RAY DIFFRACTION2chain 'D' and (resid 63 through 176 )D63 - 176
3X-RAY DIFFRACTION3chain 'D' and (resid 177 through 231 )D177 - 231
4X-RAY DIFFRACTION4chain 'D' and (resid 232 through 313 )D232 - 313

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