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- PDB-8igx: SARS-CoV-2 3CL protease (3CLpro) in complex with compound 9 (simn... -

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Basic information

Entry
Database: PDB / ID: 8igx
TitleSARS-CoV-2 3CL protease (3CLpro) in complex with compound 9 (simnotrelvir, SIM0417, SSD8432)
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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / methylation / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / lipid binding / host cell nucleus / 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 / 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. / : / : / Coronavirus replicase NSP7 / Coronavirus 3Ecto 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 (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) 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 replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-PQL / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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 21, 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)34,3752
Polymers33,8261
Non-polymers5501
Water3,009167
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7504
Polymers67,6512
Non-polymers1,0992
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area3140 Å2
ΔGint-13 kcal/mol
Surface area24510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.578, 62.831, 105.323
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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-PQL / (8~{S})-~{N}-[(1~{S})-1-cyano-2-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]ethyl]-7-[(2~{S})-3,3-dimethyl-2-[2,2,2-tris(fluoranyl)ethanoylamino]butanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxamide


Mass: 549.630 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H30F3N5O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.23 Å3/Da / Density % sol: 44.82 %
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: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 24550 / % possible obs: 99.7 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.991 / Χ2: 0.068 / Net I/σ(I): 2.5 / Num. measured all: 308615
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.9-1.975.81.11745770.406199.8
1.97-2.056.30.91346470.413199.9
2.05-2.146.70.78446130.422199.9
2.14-2.256.80.63246200.431100
2.25-2.396.30.43246100.435199.4
2.39-2.587.20.32946080.4351100
2.58-2.847.20.23346330.44199.9
2.84-3.2570.13846010.429199.9
3.25-4.096.80.07645950.4199.2
4.09-506.90.05545760.322198.9

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
HKL-2000data scaling
PHASERphasing
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→21.43 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 20.64 / Stereochemistry target values: ML
Details: Some reflections are excluded from the scaling process.
RfactorNum. reflection% reflection
Rfree0.2125 1182 4.82 %
Rwork0.176 --
obs0.1778 24517 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→21.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2327 0 36 167 2530
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072426
X-RAY DIFFRACTIONf_angle_d0.8973308
X-RAY DIFFRACTIONf_dihedral_angle_d11.927870
X-RAY DIFFRACTIONf_chiral_restr0.055378
X-RAY DIFFRACTIONf_plane_restr0.005427
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.980.26361490.20692857X-RAY DIFFRACTION99
1.98-2.090.25141420.1972871X-RAY DIFFRACTION100
2.09-2.220.23391430.18912890X-RAY DIFFRACTION100
2.22-2.390.20851330.1842894X-RAY DIFFRACTION99
2.39-2.630.22961330.19062910X-RAY DIFFRACTION100
2.63-3.010.27051570.19742922X-RAY DIFFRACTION100
3.01-3.790.20751660.17362903X-RAY DIFFRACTION99
3.79-21.430.1661590.14833088X-RAY DIFFRACTION99
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)
10.0508-0.00030.00020.1031-0.08920.0995-0.004-0.0089-0.0499-0.012-0.0301-0.03030.0344-0.022400.1194-0.02940.01360.1328-0.02120.1089-8.266522.056-37.1963
2-0.01030.0169-0.011-0.00560.00570.0014-0.1336-0.0632-0.07310.07690.25780.05910.1235-0.1559-0-0.0243-0.5229-0.1368-0.0733-0.17490.2345-25.5198.3391-35.039
30.00760.0197-0.00090.01960.00830.0189-0.07340.12850.0417-0.099-0.02120.04790.0064-0.187500.2456-0.0434-0.03060.2439-0.05620.1828-17.635416.8169-47.9475
40.01990.0296-0.01290.0544-0.02160.02030.03040.1188-0.105-0.07560.0002-0.07810.19830.091500.207-0.00110.0270.1707-0.03470.1631-4.073714.5729-40.1562
50.01190.01160.00870.00710.0156-0.0103-0.04910.0130.02890.0071-0.0592-0.0051-0.06240.059500.1138-0.0032-0.0080.14-0.00210.1404-6.154126.0749-30.4477
60.01380.09590.04890.06510.03270.06430.00130.0329-0.05310.0452-0.00210.01960.0495-0.060400.0978-0.0060.02130.0839-0.01530.0893-6.575117.5858-27.9608
70.0427-0.07230.0407-0.00360.01250.0387-0.0514-0.1695-0.0142-0.07050.0015-0.00760.0146-0.0715-00.1031-0.01160.00220.10920.02350.0872-1.809515.7212-17.6192
80.1610.03620.07770.04970.00720.0853-0.0046-0.0736-0.0782-0.006-0.0009-0.0311-0.0127-0.0074-00.10810.0130.00520.11120.02960.129714.647318.1382-7.7251
90.0746-0.0122-0.01120.0309-0.01040.0044-0.04440.05820.0369-0.09890.07810.0374-0.1105-0.05800.09360.00830.00570.10420.00160.11288.575627.2072-15.1779
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 62 )
3X-RAY DIFFRACTION3chain 'A' and (resid 63 through 83 )
4X-RAY DIFFRACTION4chain 'A' and (resid 84 through 110 )
5X-RAY DIFFRACTION5chain 'A' and (resid 111 through 129 )
6X-RAY DIFFRACTION6chain 'A' and (resid 130 through 180 )
7X-RAY DIFFRACTION7chain 'A' and (resid 181 through 213 )
8X-RAY DIFFRACTION8chain 'A' and (resid 214 through 274 )
9X-RAY DIFFRACTION9chain 'A' and (resid 275 through 302 )

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