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- PDB-8ifr: SARS-CoV-2 3CL protease (3CLpro) in complex with compound 3 -

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Basic information

Entry
Database: PDB / ID: 8ifr
TitleSARS-CoV-2 3CL protease (3CLpro) in complex with compound 3
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / Mpro / Viral protein-inhibitor 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-P0O / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsSu, H.X. / Zhao, W.F. / Xie, H. / Nie, T.Q. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.
Authors: Jiang, X. / Su, H. / Shang, W. / Zhou, F. / Zhang, Y. / Zhao, W. / Zhang, Q. / Xie, H. / Jiang, L. / Nie, T. / Yang, F. / Xiong, M. / Huang, X. / Li, M. / Chen, P. / Peng, S. / Xiao, G. / ...Authors: Jiang, X. / Su, H. / Shang, W. / Zhou, F. / Zhang, Y. / Zhao, W. / Zhang, Q. / Xie, H. / Jiang, L. / Nie, T. / Yang, F. / Xiong, M. / Huang, X. / Li, M. / Chen, P. / Peng, S. / Xiao, G. / Jiang, H. / Tang, R. / Zhang, L. / Shen, J. / Xu, Y.
History
DepositionFeb 19, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2May 8, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3712
Polymers33,8261
Non-polymers5461
Water3,999222
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7434
Polymers67,6512
Non-polymers1,0912
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area3080 Å2
ΔGint-14 kcal/mol
Surface area24380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.582, 63.707, 105.502
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-582-

HOH

21A-684-

HOH

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Components

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


Mass: 33825.547 Da / Num. of mol.: 1
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-P0O / (1R,2S,5S)-3-[(2S)-2-(tert-butylcarbamoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-N-[(2S)-5-oxidanylidene-1-[(3S)-2-oxidanylidenepyrrolidin-3-yl]hex-3-en-2-yl]-3-azabicyclo[3.1.0]hexane-2-carboxamide


Mass: 545.714 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H47N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 222 / 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: 2.26 Å3/Da / Density % sol: 45.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, pH5.5-6.5, 10%-25% PEG6000, 3% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Nov 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.66→54.54 Å / Num. obs: 36606 / % possible obs: 99.1 % / Redundancy: 9.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.131 / Rpim(I) all: 0.046 / Rrim(I) all: 0.14 / Χ2: 0.94 / Net I/σ(I): 13.2 / Num. measured all: 342897
Reflection shellResolution: 1.66→1.75 Å / % possible obs: 97.8 % / Redundancy: 9.9 % / Rmerge(I) obs: 1.367 / Num. measured all: 51192 / Num. unique obs: 5186 / CC1/2: 0.635 / Rpim(I) all: 0.46 / Rrim(I) all: 1.444 / Χ2: 0.86 / Net I/σ(I) obs: 2.5

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→30.79 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 21.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2157 1851 5.06 %
Rwork0.1812 --
obs0.1829 36567 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.66→30.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2323 0 39 222 2584
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062419
X-RAY DIFFRACTIONf_angle_d0.8533299
X-RAY DIFFRACTIONf_dihedral_angle_d14.315865
X-RAY DIFFRACTIONf_chiral_restr0.052378
X-RAY DIFFRACTIONf_plane_restr0.006426
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.66-1.710.31731450.2992579X-RAY DIFFRACTION98
1.71-1.760.3111510.2712587X-RAY DIFFRACTION98
1.76-1.810.27831400.25112608X-RAY DIFFRACTION99
1.81-1.880.271410.22042650X-RAY DIFFRACTION99
1.88-1.950.24311440.20642610X-RAY DIFFRACTION99
1.95-2.040.2181430.19792628X-RAY DIFFRACTION99
2.04-2.150.20771360.18272655X-RAY DIFFRACTION99
2.15-2.290.23981270.18712679X-RAY DIFFRACTION99
2.29-2.460.24371520.18932658X-RAY DIFFRACTION100
2.46-2.710.22761320.18812708X-RAY DIFFRACTION100
2.71-3.10.22241360.18372717X-RAY DIFFRACTION100
3.1-3.910.19931530.16442746X-RAY DIFFRACTION100
3.91-30.790.17061510.14932891X-RAY DIFFRACTION100
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)
11.79210.4541.24151.28180.28272.3951-0.11120.1812-0.0198-0.14250.03410.07110.00140.04990.07340.16320.00360.01890.1471-0.02190.1506-7.947622.225-37.1629
20.90540.869-0.69141.756-1.81812.49940.01070.1408-0.015-0.15750.16140.45610.3414-0.4679-0.21410.3156-0.1061-0.03270.3676-0.0560.3542-23.006511.3963-39.3099
32.04250.8634-0.26261.2797-0.26673.0251-0.1720.3392-0.1001-0.29610.17420.05640.2985-0.1411-0.03670.2874-0.01590.00140.254-0.06620.1985-11.230215.8934-47.021
41.6470.24680.84121.6692-0.35293.1307-0.02020.1404-0.1296-0.0154-0.049-0.07510.04920.31040.07070.13640.00320.01430.152-0.0180.1555-4.190520.1101-29.3955
53.73440.91181.42865.1126-1.33692.14850.0224-0.1024-0.40750.1573-0.1202-0.1420.37460.00330.05160.18520.0039-0.00170.17230.0250.1765-8.673412.2819-25.9342
63.40480.55261.98790.15860.4761.32830.1258-0.432-0.12360.0486-0.13320.0670.156-0.2562-0.02560.1916-0.0070.03320.19120.01320.1846-0.078217.4216-16.025
73.33540.2932-0.24012.05670.66292.2281-0.0262-0.2988-0.2320.23870.0157-0.13060.26620.01620.0110.19430.0256-0.00080.19010.04230.203714.990118.615-7.5568
83.86170.1265-0.54373.3082-0.24422.20020.00320.23780.3893-0.14250.17530.2257-0.2293-0.164-0.22390.17110.0124-0.0050.17420.05030.24459.122827.8574-16.9502
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 43 )
2X-RAY DIFFRACTION2chain 'A' and (resid 44 through 70 )
3X-RAY DIFFRACTION3chain 'A' and (resid 71 through 99 )
4X-RAY DIFFRACTION4chain 'A' and (resid 100 through 167 )
5X-RAY DIFFRACTION5chain 'A' and (resid 168 through 185 )
6X-RAY DIFFRACTION6chain 'A' and (resid 186 through 213 )
7X-RAY DIFFRACTION7chain 'A' and (resid 214 through 274 )
8X-RAY DIFFRACTION8chain 'A' and (resid 275 through 305 )

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