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- PDB-8cyz: Crystal structure of SARS-CoV-2 Mpro with compound C4 -

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Entry
Database: PDB / ID: 8cyz
TitleCrystal structure of SARS-CoV-2 Mpro with compound C4
Components3C-like proteinase
KeywordsVIRAL PROTEIN / Hydrolase / 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 / host cell endosome / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / 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 / symbiont-mediated suppression of host NF-kappaB cascade / host cell Golgi apparatus / DNA helicase / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase 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 / symbiont-mediated activation of host autophagy / viral translational frameshifting / 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-P6I / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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)137,0588
Polymers135,3024
Non-polymers1,7564
Water11,025612
1
A: 3C-like proteinase
C: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5294
Polymers67,6512
Non-polymers8782
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3110 Å2
ΔGint-16 kcal/mol
Surface area25020 Å2
MethodPISA
2
B: 3C-like proteinase
D: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5294
Polymers67,6512
Non-polymers8782
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3120 Å2
ΔGint-17 kcal/mol
Surface area24900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.430, 102.620, 102.220
Angle α, β, γ (deg.)90.000, 100.190, 90.000
Int Tables number4
Space group name H-MP1211
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 / End auth comp-ID: PHE / End label comp-ID: PHE / Refine code: _ / Auth seq-ID: 1 - 305 / Label seq-ID: 1 - 305

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

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-P6I / N-[(4-chlorothiophen-2-yl)methyl]-2-(isoquinolin-4-yl)-N-[4-(methylsulfanyl)phenyl]acetamide


Mass: 438.993 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H19ClN2OS2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 612 / 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: 52.19 %
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: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 1.1806 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1806 Å / Relative weight: 1
ReflectionResolution: 1.9→45.75 Å / Num. obs: 107595 / % possible obs: 99.8 % / Redundancy: 6.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.185 / Rpim(I) all: 0.077 / Rrim(I) all: 0.201 / Net I/σ(I): 7.1
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
1.9-1.936.52.4733477353250.4641.0392.6870.899.7
10.41-45.716.40.03743986840.9990.0160.0429.598.5

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JOY

7joy


Resolution: 1.9→45.75 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.928 / SU B: 7.544 / SU ML: 0.192 / SU R Cruickshank DPI: 0.1965 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.197 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2776 5470 5.1 %RANDOM
Rwork0.2447 ---
obs0.2464 102124 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 104.09 Å2 / Biso mean: 31.359 Å2 / Biso min: 13.54 Å2
Baniso -1Baniso -2Baniso -3
1--1.9 Å2-0 Å2-0.33 Å2
2---1.19 Å2-0 Å2
3---3.01 Å2
Refinement stepCycle: final / Resolution: 1.9→45.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9432 0 116 612 10160
Biso mean--31.85 34.69 -
Num. residues----1220
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0139940
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179140
X-RAY DIFFRACTIONr_angle_refined_deg1.5461.65713548
X-RAY DIFFRACTIONr_angle_other_deg1.3151.58621016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.68451256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.19923.223484
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.042151568
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1121544
X-RAY DIFFRACTIONr_chiral_restr0.0690.21280
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211568
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022384
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A98570.08
12B98570.08
21A96870.1
22C96870.1
31A97480.1
32D97480.1
41B96990.1
42C96990.1
51B97100.1
52D97100.1
61C98750.09
62D98750.09
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.427 411 -
Rwork0.435 7507 -
all-7918 -
obs--99.79 %

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