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- PDB-7k0h: 1.70 A resolution structure of SARS-CoV 3CL protease in complex w... -

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Basic information

Entry
Database: PDB / ID: 7k0h
Title1.70 A resolution structure of SARS-CoV 3CL protease in complex with a deuterated GC376 alpha-ketoamide analog (compound 5)
ComponentsReplicase polyprotein 1a
KeywordsHydrolase/Hydrolase Inhibitor / PROTEASE / severe acute respiratory syndrome coronavirus / SARS 3CL protease Inhhibitors / hydrolase / deuterated hydrolase inhibitor / 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
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 / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-VR4 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesHuman SARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsLovell, S. / Kashipathy, M.M. / Battaile, K.P. / Chamandi, S.D. / Nguyen, H.N. / Kim, Y. / Chang, K.O. / Groutas, W.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI109039 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.
Authors: Dampalla, C.S. / Zheng, J. / Perera, K.D. / Wong, L.R. / Meyerholz, D.K. / Nguyen, H.N. / Kashipathy, M.M. / Battaile, K.P. / Lovell, S. / Kim, Y. / Perlman, S. / Groutas, W.C. / Chang, K.O.
History
DepositionSep 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Replicase polyprotein 1a
B: Replicase polyprotein 1a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,2637
Polymers68,9212
Non-polymers1,3425
Water5,368298
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint-20 kcal/mol
Surface area24880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.030, 98.975, 59.666
Angle α, β, γ (deg.)90.000, 107.970, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Replicase polyprotein 1a / pp1a / ORF1a polyprotein


Mass: 34460.297 Da / Num. of mol.: 2 / Fragment: Full Length
Source method: isolated from a genetically manipulated source
Details: N-terminal hexahistidine tag / Source: (gene. exp.) Human SARS coronavirus / Gene: 1a / Plasmid: pET28 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P0C6U8, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, SARS coronavirus main proteinase
#2: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-VR4 / N-{(2S,3R)-4-(benzylamino)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-N~2~-[(benzyloxy)carbonyl]-L-leucinamide / GC376 alpha-ketoamide analog (bound form)


Mass: 538.635 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H38N4O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 298 / Source method: isolated from a natural source / Formula: H2O
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: 2.24 Å3/Da / Density % sol: 45.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 30% (w/v) PEG 3350, 0.1 M Tris, 0.4 M sodium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 9, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→49.49 Å / Num. obs: 66700 / % possible obs: 99.9 % / Redundancy: 4.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.067 / Net I/σ(I): 10.5 / Num. measured all: 283870
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.7-1.734.40.7511534635170.8222100
9-49.494.20.04419894760.99726.599.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.33 Å49.49 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
PHENIX1.18.1_3863refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6W2A

6w2a


Resolution: 1.7→46.27 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.02 / Phase error: 23.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.21 3304 4.96 %
Rwork0.1743 63330 -
obs0.1762 66634 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.47 Å2 / Biso mean: 32.4559 Å2 / Biso min: 15.15 Å2
Refinement stepCycle: final / Resolution: 1.7→46.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4492 0 87 298 4877
Biso mean--33.87 38.42 -
Num. residues----598
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.720.30551310.256126472778100
1.72-1.750.28511450.243625942739100
1.75-1.780.28431260.235126602786100
1.78-1.810.24291370.22626172754100
1.81-1.840.24691460.221226072753100
1.84-1.870.24261360.206426492785100
1.87-1.910.23681200.202526322752100
1.91-1.950.25871200.200326632783100
1.95-1.990.24151410.194826542795100
1.99-2.030.21081440.19126162760100
2.03-2.090.24061470.193726002747100
2.09-2.140.20281350.178226462781100
2.14-2.20.23411290.18126582787100
2.2-2.280.21671240.182426432767100
2.28-2.360.23771330.175926442777100
2.36-2.450.20131430.177326232766100
2.45-2.560.21391340.170426462780100
2.56-2.70.21771410.176326492790100
2.7-2.870.23011330.185626362769100
2.87-3.090.22241490.179926482797100
3.09-3.40.22541410.175826382779100
3.4-3.890.19651700.15372602277299
3.89-4.90.14561470.134626602807100
4.9-46.270.20851320.174126982830100

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