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- PDB-7neo: Crystal Structure of SARS-CoV-2 main protease (Nsp5) in complex w... -

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Entry
Database: PDB / ID: 7neo
TitleCrystal Structure of SARS-CoV-2 main protease (Nsp5) in complex with compound 15
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / Inhibitor / complex / protease
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 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 ...protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 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 / TRAF3-dependent IRF activation pathway / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / symbiont-mediated suppression of host NF-kappaB cascade / host cell endosome / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA (guanine-N7)-methyltransferase / omega peptidase activity / methyltransferase cap1 / 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 / DNA helicase / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / 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 / lyase activity / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / lipid binding / DNA-templated transcription / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / 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 Nonstructural protein 13, 1B domain ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / 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 Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 Interface domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) 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 / Nidovirus 2-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus 3'-5' exoribonuclease domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / 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 / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / 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.
Similarity search - Domain/homology
Chem-U9H / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsTalibov, V.O.
CitationJournal: J.Am.Chem.Soc. / Year: 2022
Title: Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses.
Authors: Luttens, A. / Gullberg, H. / Abdurakhmanov, E. / Vo, D.D. / Akaberi, D. / Talibov, V.O. / Nekhotiaeva, N. / Vangeel, L. / De Jonghe, S. / Jochmans, D. / Krambrich, J. / Tas, A. / Lundgren, B. ...Authors: Luttens, A. / Gullberg, H. / Abdurakhmanov, E. / Vo, D.D. / Akaberi, D. / Talibov, V.O. / Nekhotiaeva, N. / Vangeel, L. / De Jonghe, S. / Jochmans, D. / Krambrich, J. / Tas, A. / Lundgren, B. / Gravenfors, Y. / Craig, A.J. / Atilaw, Y. / Sandstrom, A. / Moodie, L.W.K. / Lundkvist, A. / van Hemert, M.J. / Neyts, J. / Lennerstrand, J. / Kihlberg, J. / Sandberg, K. / Danielson, U.H. / Carlsson, J.
History
DepositionFeb 4, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: 3C-like proteinase nsp5
BBB: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,77711
Polymers67,6512
Non-polymers1,1269
Water8,863492
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-2 kcal/mol
Surface area25390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.572, 53.822, 114.768
Angle α, β, γ (deg.)90.000, 100.492, 90.000
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.: 2
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 BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-U9H / 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione / 2-cyclobutyl-7-(5-fluoranylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione


Mass: 289.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H16FN3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 492 / 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: 2.01 Å3/Da / Density % sol: 38.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.75
Details: 100 nL protein (8.3 mg/mL, 50 mM Tris pH 8.0, 300 mM NaCl), 50 nL seeds, 450 nL reservoir (200 mM HEPES pH 7.75, 5% DMSO, 12.5% PEG4K). Soaking: 200 mM HEPES pH 7.75, 12 mM compound, 5% ...Details: 100 nL protein (8.3 mg/mL, 50 mM Tris pH 8.0, 300 mM NaCl), 50 nL seeds, 450 nL reservoir (200 mM HEPES pH 7.75, 5% DMSO, 12.5% PEG4K). Soaking: 200 mM HEPES pH 7.75, 12 mM compound, 5% DMSO, 10% PEG300, 20% PEG3K, RT, 2 h.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.976 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.64→48.67 Å / Num. obs: 65712 / % possible obs: 99.9 % / Redundancy: 5.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.045 / Rrim(I) all: 0.079 / Net I/σ(I): 11.3
Reflection shellResolution: 1.64→1.67 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.431 / Mean I/σ(I) obs: 3.2 / Num. unique obs: 3232 / CC1/2: 0.94 / Rpim(I) all: 0.302 / Rrim(I) all: 0.529 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimless0.7.4data scaling
XDSb. 20200131data reduction
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7B2J

7b2j


Resolution: 1.64→48.627 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.314 / SU ML: 0.08 / Cross valid method: FREE R-VALUE / ESU R: 0.121 / ESU R Free: 0.116
RfactorNum. reflection% reflection
Rfree0.2387 3193 4.86 %
Rwork0.2012 62501 -
all0.203 --
obs-65694 99.919 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 18.668 Å2
Baniso -1Baniso -2Baniso -3
1--0.87 Å2-0 Å2-0.586 Å2
2---0.339 Å2-0 Å2
3---1.335 Å2
Refinement stepCycle: LAST / Resolution: 1.64→48.627 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4716 0 70 492 5278
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0134964
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174603
X-RAY DIFFRACTIONr_angle_refined_deg1.7041.646759
X-RAY DIFFRACTIONr_angle_other_deg1.5071.57510577
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2915624
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.72123.171246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.87815788
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7151522
X-RAY DIFFRACTIONr_chiral_restr0.0880.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.010.025742
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021176
X-RAY DIFFRACTIONr_nbd_refined0.2080.2945
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1870.24376
X-RAY DIFFRACTIONr_nbtor_refined0.1750.22414
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.22306
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2399
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1030.214
X-RAY DIFFRACTIONr_nbd_other0.2150.279
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2140.228
X-RAY DIFFRACTIONr_mcbond_it1.7671.742478
X-RAY DIFFRACTIONr_mcbond_other1.7671.7392477
X-RAY DIFFRACTIONr_mcangle_it2.5442.6073108
X-RAY DIFFRACTIONr_mcangle_other2.5432.6083109
X-RAY DIFFRACTIONr_scbond_it2.6342.0542486
X-RAY DIFFRACTIONr_scbond_other2.6332.0552487
X-RAY DIFFRACTIONr_scangle_it3.9542.953643
X-RAY DIFFRACTIONr_scangle_other3.9542.9513644
X-RAY DIFFRACTIONr_lrange_it5.51821.9265569
X-RAY DIFFRACTIONr_lrange_other5.48321.4795445
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.64-1.6830.272440.2434588X-RAY DIFFRACTION99.9173
1.683-1.7290.2652140.2294473X-RAY DIFFRACTION99.9573
1.729-1.7790.2612180.2114364X-RAY DIFFRACTION99.9346
1.779-1.8340.2612100.2174261X-RAY DIFFRACTION99.8883
1.834-1.8940.2751950.214128X-RAY DIFFRACTION99.9538
1.894-1.960.2451770.1973965X-RAY DIFFRACTION99.9035
1.96-2.0340.2322030.1913842X-RAY DIFFRACTION100
2.034-2.1170.2422160.1933700X-RAY DIFFRACTION99.949
2.117-2.2110.2591590.23526X-RAY DIFFRACTION99.9187
2.211-2.3190.2291780.1893394X-RAY DIFFRACTION99.972
2.319-2.4440.231810.1963212X-RAY DIFFRACTION99.9117
2.444-2.5930.2421520.2043066X-RAY DIFFRACTION99.8139
2.593-2.7720.231550.2062866X-RAY DIFFRACTION99.9008
2.772-2.9930.241630.1972648X-RAY DIFFRACTION99.9289
2.993-3.2790.2371240.1982467X-RAY DIFFRACTION99.9229
3.279-3.6660.2031110.22253X-RAY DIFFRACTION99.9577
3.666-4.2320.2311010.1881980X-RAY DIFFRACTION100
4.232-5.1810.244850.1881685X-RAY DIFFRACTION100

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