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- PDB-8y42: Crystal structure of SARS-CoV-2 3CL protease (3CLpro) in complex ... -

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Entry
Database: PDB / ID: 8y42
TitleCrystal structure of SARS-CoV-2 3CL protease (3CLpro) in complex with compound 51
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / Mpro / VIRAL PROTEIN-inhibitor complex
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / endonuclease activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome ...viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / endonuclease activity / 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 / methylation / 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 / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / 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 / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / symbiont-mediated activation of host autophagy / viral translational frameshifting / 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
Coronavirus replicase NSP2, C-terminal / 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 ...Coronavirus replicase NSP2, C-terminal / 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. / Coronavirus replicase NSP7 / : / : / Coronavirus Nsp3 ectodomain (3Ecto) 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
: / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsNie, T.Q. / Su, H.X. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CL pro Inhibitors as anti-SARS-CoV-2 Drug Candidate.
Authors: Jiang, Z. / Feng, B. / Chen, L. / Nie, T. / Chen, S. / Wang, L. / Liu, H. / Yu, T. / Zhang, Y. / Zheng, M. / Xu, Y. / Liu, H. / Zang, Y. / Su, H. / Zhang, L. / Li, J. / Zhou, Y.
History
DepositionJan 30, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2025Group: Database references / Structure summary / Category: citation / citation_author / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _struct.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
B: 3C-like proteinase nsp5
C: 3C-like proteinase nsp5
D: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,3168
Polymers135,3024
Non-polymers2,0144
Water1,13563
1
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6584
Polymers67,6512
Non-polymers1,0072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2650 Å2
ΔGint-13 kcal/mol
Surface area24050 Å2
MethodPISA
2
C: 3C-like proteinase nsp5
hetero molecules

D: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6584
Polymers67,6512
Non-polymers1,0072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_645-x+1,y-1/2,-z1
Buried area2800 Å2
ΔGint-14 kcal/mol
Surface area24360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.490, 107.840, 116.340
Angle α, β, γ (deg.)90.00, 101.08, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 4
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-A1D51 / ~{N}-[(1~{S},2~{R})-2-[[4-cyclopropyl-2-(methylcarbamoyl)-6-nitro-phenyl]amino]cyclohexyl]-2-oxidanylidene-1~{H}-quinoline-4-carboxamide


Mass: 503.550 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H29N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.07 Å3/Da / Density % sol: 40.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, pH5.5-7.0, 5%-25% PEG6000, 3% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.35→25.23 Å / Num. obs: 45825 / % possible obs: 99.7 % / Redundancy: 6.6 % / CC1/2: 0.991 / Rmerge(I) obs: 0.301 / Rpim(I) all: 0.127 / Rrim(I) all: 0.327 / Χ2: 0.97 / Net I/σ(I): 5.7 / Num. measured all: 304622
Reflection shellResolution: 2.35→2.41 Å / % possible obs: 99.8 % / Redundancy: 6.8 % / Rmerge(I) obs: 1.683 / Num. measured all: 23168 / Num. unique obs: 3401 / CC1/2: 0.533 / Rpim(I) all: 0.694 / Rrim(I) all: 1.823 / Χ2: 0.98 / Net I/σ(I) obs: 1.5

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660: ???)refinement
Aimlessdata scaling
PHASERphasing
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.35→24.38 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2743 2147 4.71 %
Rwork0.2263 --
obs0.2286 45631 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.35→24.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8961 0 148 63 9172
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029325
X-RAY DIFFRACTIONf_angle_d0.47412732
X-RAY DIFFRACTIONf_dihedral_angle_d13.9593282
X-RAY DIFFRACTIONf_chiral_restr0.041456
X-RAY DIFFRACTIONf_plane_restr0.0041647
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.40.38141740.33492889X-RAY DIFFRACTION100
2.4-2.460.39451320.31852859X-RAY DIFFRACTION100
2.46-2.530.34991590.30352937X-RAY DIFFRACTION100
2.53-2.610.33991130.27742898X-RAY DIFFRACTION100
2.61-2.690.34611190.27262959X-RAY DIFFRACTION100
2.69-2.790.30071440.26152873X-RAY DIFFRACTION100
2.79-2.90.34731430.27082902X-RAY DIFFRACTION100
2.9-3.030.32011460.25442914X-RAY DIFFRACTION100
3.03-3.190.29231260.24592892X-RAY DIFFRACTION100
3.19-3.390.2841470.23672905X-RAY DIFFRACTION100
3.39-3.650.2771630.21942903X-RAY DIFFRACTION100
3.65-4.010.23661210.20352924X-RAY DIFFRACTION99
4.01-4.590.2331620.17052904X-RAY DIFFRACTION100
4.59-5.770.22531380.18792921X-RAY DIFFRACTION100
5.77-24.380.20391600.17622804X-RAY DIFFRACTION95

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