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- PDB-7vvt: SARS-CoV-2 3CL protease (3CLpro) in complex with a covalent inhibitor -

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Basic information

Entry
Database: PDB / ID: 7vvt
TitleSARS-CoV-2 3CL protease (3CLpro) in complex with a covalent inhibitor
Components3C-like proteinase
KeywordsVIRAL INHIBITOR/COMPLEX / Main protease / covalent inhibitor / VIRAL PROTEIN-INHIBITOR COMPLEX / VIRAL INHIBITOR-COMPLEX complex
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / 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 / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / lipid binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
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 / Carbamoyl-phosphate synthase subdomain signature 2. ...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 / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus replicase NSP7 / Peptidase family C16 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 Nsp4 C-terminal (Nsp4C) 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 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-80X / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.51 Å
AuthorsSu, H. / Nie, T. / Li, M. / Xu, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease.
Authors: Xiong, M. / Nie, T. / Shao, Q. / Li, M. / Su, H. / Xu, Y.
History
DepositionNov 8, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,2714
Polymers67,6512
Non-polymers6192
Water99155
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, native MS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint-12 kcal/mol
Surface area24030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.992, 90.120, 103.175
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein 3C-like proteinase / main protease


Mass: 33825.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-80X / N-(3-chlorophenyl)-2-[(2R)-1-ethanoyl-3-oxidanylidene-piperazin-2-yl]ethanamide


Mass: 309.748 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.34 Å3/Da / Density % sol: 47.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, pH 6, 15% PEG6000, 3% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 22080 / % possible obs: 99.2 % / Redundancy: 12.7 % / Rmerge(I) obs: 0.327 / Rpim(I) all: 0.094 / Rrim(I) all: 0.341 / Χ2: 0.435 / Net I/σ(I): 1.6 / Num. measured all: 280551
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.5912.62.28321600.5690.6562.3780.41199.5
2.59-2.6912.41.74521640.630.5071.8190.40999.7
2.69-2.8211.41.33621550.7160.4071.3990.41197.5
2.82-2.9613.51.08321760.8560.3051.1260.42299.3
2.96-3.1513.70.7521950.9280.2080.7790.44100
3.15-3.3913.40.52922200.960.1490.550.443100
3.39-3.73130.31922140.9820.0910.3320.466100
3.73-4.2711.70.17822130.9910.0530.1860.4898.9
4.27-5.3813.40.12822480.9970.0360.1330.462100
5.38-5011.90.08723350.9980.0260.0910.39797.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.77 Å26.25 Å
Translation4.77 Å26.25 Å

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Processing

Software
NameVersionClassification
HKL-3000data scaling
PHASER2.8.3phasing
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6M2N

6m2n


Resolution: 2.51→26.25 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2527 1089 4.95 %
Rwork0.2339 20921 -
obs0.2349 22010 98.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 130.31 Å2 / Biso mean: 50.7034 Å2 / Biso min: 21.84 Å2
Refinement stepCycle: final / Resolution: 2.51→26.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4276 0 42 55 4373
Biso mean--70.03 41.89 -
Num. residues----586
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.51-2.620.37871270.33872472259995
2.62-2.760.37281350.319825852720100
2.76-2.930.32811390.29932554269398
2.93-3.160.30691360.275926032739100
3.16-3.480.26821230.240726462769100
3.48-3.980.20041450.216826542799100
3.98-5.010.19131470.1832642278999
5.01-26.250.25411370.20632765290298
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)
10.23930.13930.28150.34680.2160.6610.0153-0.0029-0.00260.027-0.0538-0.0260.00920.077200.2154-0.01820.01520.22620.01480.239424.23658.67587.862
20.47020.37280.39920.2207-0.03240.01330.0847-0.0668-0.10110.0004-0.0474-0.00060.008-0.0061-00.19680.00280.00550.21440.04420.207612.89793.944913.7014
30.1730.1407-0.31430.2506-0.02640.2244-0.00950.08350.04560.02090.07640.07650.0568-0.046600.2461-0.03990.00830.38590.03720.261-12.82537.513419.6716
40.37890.0833-0.16110.47620.31030.37030.05170.1037-0.0153-0.036-0.0080.0227-0.19930.0361-00.31320.0278-0.02810.24810.02430.2459-3.324414.3291-17.6792
5-0.01750.52760.37180.00260.0140.57-0.0016-0.02410.04960.02830.00970.0108-0.0593-0.26700.2696-0.01690.00010.3029-0.01530.2941-5.36773.5521-11.9783
60.0903-0.0706-0.03670.20160.08170.14530.2505-0.63220.01370.0521-0.2361-0.35940.3141-0.4235-00.5101-0.0722-0.12630.22380.07490.4237-2.0963-18.26872.8756
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 110 )A1 - 110
2X-RAY DIFFRACTION2chain 'A' and (resid 111 through 200 )A111 - 200
3X-RAY DIFFRACTION3chain 'A' and (resid 201 through 300 )A201 - 300
4X-RAY DIFFRACTION4chain 'B' and (resid 1 through 83 )B1 - 83
5X-RAY DIFFRACTION5chain 'B' and (resid 84 through 200 )B84 - 200
6X-RAY DIFFRACTION6chain 'B' and (resid 201 through 301 )B201 - 301

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