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- PDB-8cz7: Crystal structure of SARS-CoV-2 Mpro with compound C2 -

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Basic information

Entry
Database: PDB / ID: 8cz7
TitleCrystal structure of SARS-CoV-2 Mpro with compound C2
Components3C-like proteinase
KeywordsVIRAL PROTEIN / COVID-19 / SARS-CoV-2 / protease / inhibitor
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / mRNA guanylyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / mRNA guanylyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / symbiont-mediated suppression of host toll-like receptor signaling pathway / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / copper ion binding / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Trypsin-like serine proteases / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Trypsin-like serine proteases / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / Thrombin, subunit H / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / 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 single-stranded poly(A) binding domain / 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / : / Coronavirus replicase NSP2, N-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.
Similarity search - Domain/homology
Chem-P7L / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsWorrall, L.J. / Lee, J. / Strynadka, N.C.J.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Emerg Microbes Infect / Year: 2023
Title: A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.
Authors: Perez-Vargas, J. / Worrall, L.J. / Olmstead, A.D. / Ton, A.T. / Lee, J. / Villanueva, I. / Thompson, C.A.H. / Dudek, S. / Ennis, S. / Smith, J.R. / Shapira, T. / De Guzman, J. / Gang, S. / ...Authors: Perez-Vargas, J. / Worrall, L.J. / Olmstead, A.D. / Ton, A.T. / Lee, J. / Villanueva, I. / Thompson, C.A.H. / Dudek, S. / Ennis, S. / Smith, J.R. / Shapira, T. / De Guzman, J. / Gang, S. / Ban, F. / Vuckovic, M. / Bielecki, M. / Kovacic, S. / Kenward, C. / Hong, C.Y. / Gordon, D.G. / Levett, P.N. / Krajden, M. / Leduc, R. / Boudreault, P.L. / Niikura, M. / Paetzel, M. / Young, R.N. / Cherkasov, A. / Strynadka, N.C.J. / Jean, F.
History
DepositionMay 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release

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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
C: 3C-like proteinase
D: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,9948
Polymers135,3024
Non-polymers1,6924
Water7,278404
1
A: 3C-like proteinase
C: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4974
Polymers67,6512
Non-polymers8462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3120 Å2
ΔGint-14 kcal/mol
Surface area24850 Å2
MethodPISA
2
B: 3C-like proteinase
D: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4974
Polymers67,6512
Non-polymers8462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-16 kcal/mol
Surface area24760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.574, 67.470, 93.099
Angle α, β, γ (deg.)74.950, 80.030, 66.730
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: SER / Beg label comp-ID: SER / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PHEPHEAA1 - 3051 - 305
21PHEPHEBB1 - 3051 - 305
12THRTHRAA1 - 3041 - 304
22THRTHRCC1 - 3041 - 304
13THRTHRAA1 - 3041 - 304
23THRTHRDD1 - 3041 - 304
14THRTHRBB1 - 3041 - 304
24THRTHRCC1 - 3041 - 304
15THRTHRBB1 - 3041 - 304
25THRTHRDD1 - 3041 - 304
16GLNGLNCC1 - 3061 - 306
26GLNGLNDD1 - 3061 - 306

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
3C-like proteinase / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33825.547 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical
ChemComp-P7L / N-[(4-chlorothiophen-2-yl)methyl]-2-(isoquinolin-4-yl)-N-(4-methoxyphenyl)acetamide


Mass: 422.927 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H19ClN2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 404 / 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: 2.57 Å3/Da / Density % sol: 52.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M Tris pH 8, 15 % PEG 8000, 10 % ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS3 R 200K-A / Detector: PIXEL / Date: Jun 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→25.64 Å / Num. obs: 87146 / % possible obs: 94.6 % / Redundancy: 5.1 % / CC1/2: 0.988 / Net I/σ(I): 6.62
Reflection shellResolution: 2→2.07 Å / Redundancy: 4.9 % / Mean I/σ(I) obs: 0.62 / Num. unique obs: 8486 / CC1/2: 0.79 / % possible all: 82.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
CrysalisProdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JOY

7joy


Resolution: 2→25.64 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.896 / SU B: 6.7 / SU ML: 0.173 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.245 / ESU R Free: 0.196 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2711 4381 5.1 %RANDOM
Rwork0.2419 ---
obs0.2433 82308 95.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 222.72 Å2 / Biso mean: 27.499 Å2 / Biso min: 11.41 Å2
Baniso -1Baniso -2Baniso -3
1-2.06 Å2-1.15 Å21.46 Å2
2---1.37 Å2-0.63 Å2
3----1.04 Å2
Refinement stepCycle: final / Resolution: 2→25.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9428 0 116 404 9948
Biso mean--33.96 31.4 -
Num. residues----1222
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0139916
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179108
X-RAY DIFFRACTIONr_angle_refined_deg1.5661.65713517
X-RAY DIFFRACTIONr_angle_other_deg1.3451.58520942
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.35851254
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.02923.432475
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.678151558
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7681540
X-RAY DIFFRACTIONr_chiral_restr0.0730.21280
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211550
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022366
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A97570.09
12B97570.09
21A94450.12
22C94450.12
31A94030.12
32D94030.12
41B93610.12
42C93610.12
51B93660.12
52D93660.12
61C97050.1
62D97050.1
LS refinement shellResolution: 2.002→2.054 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.373 305 -
Rwork0.349 5859 -
all-6164 -
obs--91.55 %

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