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

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Basic information

Entry
Database: PDB / ID: 7lfv
TitleCrystal structure of the SARS CoV-1 Papain-like protease in complex with peptide inhibitor VIR251
Components
  • Papain-like protease peptide inhibitor VIR251
  • papain-like protease
KeywordsHydrolase/Hydrolas Inhibitor / COVID-19 / CORONAVIRUS / SARS / COV-1 / COV-2 / PAPAIN-LIKE PROTEASE / PLPRO / DEUBIQUITINATING ENZYME / UBIQUITIN / ACTIVITY-BASED PROBE / Hydrolase-Hydrolas 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 / 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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / host cell Golgi apparatus / methylation / 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 / host cell perinuclear region of cytoplasm / regulation of autophagy / 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
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 VIR251 / AMMONIUM ION / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.23 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 / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: papain-like protease
A: papain-like protease
D: Papain-like protease peptide inhibitor VIR251
F: Papain-like protease peptide inhibitor VIR251
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,11232
Polymers74,3364
Non-polymers1,77628
Water2,180121
1
B: papain-like protease
F: Papain-like protease peptide inhibitor VIR251
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,17017
Polymers37,1682
Non-polymers1,00215
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: papain-like protease
D: Papain-like protease peptide inhibitor VIR251
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,94215
Polymers37,1682
Non-polymers77413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.610, 103.610, 265.354
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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Components

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Protein / Protein/peptide , 2 types, 4 molecules BADF

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


Mass: 36688.527 Da / Num. of mol.: 2
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 VIR251


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 479.527 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: Papain-like protease peptide inhibitor VIR251

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Non-polymers , 6 types, 149 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 21 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-NH4 / AMMONIUM ION


Mass: 18.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H4N
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.77 Å3/Da / Density % sol: 55.52 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M ammonium sulfate, 16% 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: Nov 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.23→132.68 Å / Num. obs: 42208 / % possible obs: 99.9 % / Redundancy: 38.7 % / CC1/2: 1 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.016 / Rrim(I) all: 0.101 / Net I/σ(I): 30.9 / Num. measured all: 1632487
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
2.23-2.335.62.03513526237960.7560.3412.064299.3
8.91-132.6832.70.0312685782210.0050.031113.2100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.5.32data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WUU

6wuu


Resolution: 2.23→53.34 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2346 2000 4.75 %
Rwork0.1972 40096 -
obs0.199 42096 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 199.04 Å2 / Biso mean: 65.5255 Å2 / Biso min: 31.54 Å2
Refinement stepCycle: final / Resolution: 2.23→53.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4929 0 171 121 5221
Biso mean--73 57.44 -
Num. residues----626
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.23-2.280.35181380.29652765290399
2.28-2.350.31921390.262927982937100
2.35-2.410.29031420.261428232965100
2.41-2.490.31311390.249328072946100
2.49-2.580.33051410.247528202961100
2.58-2.680.3011400.245228072947100
2.68-2.810.29111410.234128402981100
2.81-2.950.2761420.228128312973100
2.95-3.140.27781420.238828623004100
3.14-3.380.28271420.234328392981100
3.38-3.720.21571430.196228823025100
3.72-4.260.21431460.168329073053100
4.26-5.370.17641470.14729523099100
5.37-53.340.20261580.182631633321100
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)
11.0259-1.552-0.52892.70990.15971.95370.14170.319-0.3676-0.4546-0.14180.49270.2671-0.17220.08140.4883-0.0699-0.10330.5242-0.1140.6007-54.750426.1819-1.2281
20.84360.67-0.07658.5983-2.03652.1952-0.07980.087-0.1688-0.32470.21190.0320.0880.0885-0.12290.3071-0.0505-0.0050.3903-0.02570.3474-47.483245.644711.3697
34.2348-0.573-1.19155.60642.36875.14320.0589-1.75380.16881.40580.3664-0.06130.2679-0.19280.00560.82170.0246-0.00180.9327-0.06680.4913-42.930953.638738.4511
42.7444-0.40062.49282.5644-0.8724.7783-0.1958-0.43080.48480.54690.0811-0.1714-1.09830.2590.15370.7128-0.1274-0.07480.4884-0.07920.5495-40.356263.49723.3533
52.7979-2.461.86364.11190.54543.74190.21740.37230.0979-0.317-0.12680.0477-0.07940.027-0.04940.5116-0.05060.10270.62710.15490.5278-31.622364.8738-9.0516
61.32810.60880.70154.15270.25390.38120.04210.2078-0.0002-0.37260.0176-0.12990.03610.1813-0.04450.46240.04390.09450.6391-0.0190.4321-26.559541.395-6.6209
76.3481-2.37250.02481.6986-0.46950.3690.06490.355-0.9484-0.2134-0.25210.2780.2725-0.02950.13930.56060.05460.06640.4129-0.06060.6491-18.153718.8417-4.8618
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 3 through 62 )B3 - 62
2X-RAY DIFFRACTION2chain 'B' and (resid 63 through 176 )B63 - 176
3X-RAY DIFFRACTION3chain 'B' and (resid 177 through 209 )B177 - 209
4X-RAY DIFFRACTION4chain 'B' and (resid 210 through 314 )B210 - 314
5X-RAY DIFFRACTION5chain 'A' and (resid 4 through 62 )A4 - 62
6X-RAY DIFFRACTION6chain 'A' and (resid 63 through 176 )A63 - 176
7X-RAY DIFFRACTION7chain 'A' and (resid 177 through 317 )A177 - 317

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