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- PDB-7nt4: X-ray structure of SCoV2-PLpro in complex with small molecule inh... -

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Basic information

Entry
Database: PDB / ID: 7nt4
TitleX-ray structure of SCoV2-PLpro in complex with small molecule inhibitor
ComponentsNon-structural protein 3
KeywordsHYDROLASE / Drug repurposing / SCoV2-PLpro inhibitor
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / 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 / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / 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 / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / snRNP Assembly / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / 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 toll-like receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / SARS-CoV-2 modulates host translation machinery / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / regulation of autophagy / viral protein processing / lyase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / lipid binding / DNA-templated transcription / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell nucleus / 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 (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : ...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 (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 / (+) 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 / 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.
Similarity search - Domain/homology
PROFLAVIN / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsNapolitano, V. / Mourao, A. / Bostock, M. / Matsuda, A. / Czarna, A. / Popowicz, G.M.
CitationJournal: Cell Chem Biol / Year: 2022
Title: Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses.
Authors: Napolitano, V. / Dabrowska, A. / Schorpp, K. / Mourao, A. / Barreto-Duran, E. / Benedyk, M. / Botwina, P. / Brandner, S. / Bostock, M. / Chykunova, Y. / Czarna, A. / Dubin, G. / Frohlich, T. ...Authors: Napolitano, V. / Dabrowska, A. / Schorpp, K. / Mourao, A. / Barreto-Duran, E. / Benedyk, M. / Botwina, P. / Brandner, S. / Bostock, M. / Chykunova, Y. / Czarna, A. / Dubin, G. / Frohlich, T. / Holscher, M. / Jedrysik, M. / Matsuda, A. / Owczarek, K. / Pachota, M. / Plettenburg, O. / Potempa, J. / Rothenaigner, I. / Schlauderer, F. / Slysz, K. / Szczepanski, A. / Greve-Isdahl Mohn, K. / Blomberg, B. / Sattler, M. / Hadian, K. / Popowicz, G.M. / Pyrc, K.
History
DepositionMar 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Non-structural protein 3
B: Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,16322
Polymers71,8622
Non-polymers2,30120
Water3,477193
1
A: Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,06411
Polymers35,9311
Non-polymers1,13410
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,09811
Polymers35,9311
Non-polymers1,16810
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)116.370, 116.370, 253.566
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-403-

PRL

21B-401-

PRL

31A-525-

HOH

41B-583-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: PHE / Beg label comp-ID: PHE / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: _ / Auth seq-ID: 9 - 315 / Label seq-ID: 11 - 317

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Non-structural protein 3 / nsp3 / PL2-PRO / Papain-like protease / Papain-like proteinase / PL-PRO


Mass: 35930.828 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 (E. coli)
References: UniProt: P0DTD1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases

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Non-polymers , 5 types, 213 molecules

#2: Chemical
ChemComp-PRL / PROFLAVIN


Mass: 209.247 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C13H11N3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.45 Å3/Da / Density % sol: 64.39 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.05 M Sodium cacodylate pH 6.5 0.2 M Potassium chloride, 0.1 M Magnesium acetate 10 %(w/v) PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Sep 10, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.678→49.47 Å / Num. obs: 21442 / % possible obs: 95.7 % / Redundancy: 38.1 % / CC1/2: 0.99 / Net I/σ(I): 13.2
Reflection shellResolution: 2.678→2.969 Å / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1073 / CC1/2: 0.699

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6W9C

6w9c


Resolution: 2.68→49.47 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.868 / SU B: 27.963 / SU ML: 0.278 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.403 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2641 1001 4.7 %RANDOM
Rwork0.1932 ---
obs0.1965 20369 72.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 161.23 Å2 / Biso mean: 42.655 Å2 / Biso min: 2.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.76 Å2-0.38 Å2-0 Å2
2---0.76 Å20 Å2
3---2.48 Å2
Refinement stepCycle: final / Resolution: 2.68→49.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4805 0 151 193 5149
Biso mean--65.41 25.47 -
Num. residues----621
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0125116
X-RAY DIFFRACTIONr_angle_refined_deg2.0111.6516971
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.1715629
X-RAY DIFFRACTIONr_dihedral_angle_2_deg44.7623.82233
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.70715779
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8461514
X-RAY DIFFRACTIONr_chiral_restr0.1480.2674
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023955
Refine LS restraints NCS

Ens-ID: 1 / Number: 9139 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.13 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.68→2.748 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rwork0.35 88 -
obs--4.16 %
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)
12.4030.5514-0.23952.4526-0.92012.2328-0.08730.0506-0.5019-0.17260.0563-0.18260.54340.14970.0310.15760.1240.00240.3288-0.04910.111432.126735.59423.7269
21.35860.238-0.39783.4214-0.51651.41560.02940.0450.0872-0.015-0.0930.25560.1321-0.18260.06360.0325-0.01420.01310.29460.00220.036563.15837.88240.9805
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A9 - 701
2X-RAY DIFFRACTION2B4 - 401

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