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Entry
Database: PDB / ID: 8dib
TitleVirtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / SARS-CoV2 / MPro / nsp7 / COVID-19 / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 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 / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 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 / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / host cell endosome / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / mRNA guanylyltransferase / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / DNA helicase / symbiont-mediated suppression of host NF-kappaB cascade / SARS-CoV-2 modulates host translation machinery / symbiont-mediated perturbation of host ubiquitin-like protein modification / host cell Golgi apparatus / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase activity / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / 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 / DNA-templated transcription / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Trypsin-like serine proteases / 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. ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Trypsin-like serine proteases / 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. / Thrombin, subunit H / 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 / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / 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.
Similarity search - Domain/homology
Chem-TKX / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.17 Å
AuthorsSingh, I. / Shoichet, B.K.
Funding support United States, 1items
OrganizationGrant numberCountry
Other government United States
CitationJournal: Protein Sci. / Year: 2023
Title: Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.
Authors: Fink, E.A. / Bardine, C. / Gahbauer, S. / Singh, I. / Detomasi, T.C. / White, K. / Gu, S. / Wan, X. / Chen, J. / Ary, B. / Glenn, I. / O'Connell, J. / O'Donnell, H. / Fajtova, P. / Lyu, J. / ...Authors: Fink, E.A. / Bardine, C. / Gahbauer, S. / Singh, I. / Detomasi, T.C. / White, K. / Gu, S. / Wan, X. / Chen, J. / Ary, B. / Glenn, I. / O'Connell, J. / O'Donnell, H. / Fajtova, P. / Lyu, J. / Vigneron, S. / Young, N.J. / Kondratov, I.S. / Alisoltani, A. / Simons, L.M. / Lorenzo-Redondo, R. / Ozer, E.A. / Hultquist, J.F. / O'Donoghue, A.J. / Moroz, Y.S. / Taunton, J. / Renslo, A.R. / Irwin, J.J. / Garcia-Sastre, A. / Shoichet, B.K. / Craik, C.S.
History
DepositionJun 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 9, 2023Group: Database references / Category: citation / citation_author / Item: _citation.journal_volume / _citation_author.name
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 23, 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: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,3944
Polymers67,6512
Non-polymers7432
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-16 kcal/mol
Surface area24360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.911, 53.720, 115.527
Angle α, β, γ (deg.)90.000, 100.830, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11(chain A and (resid 1 through 59 or (resid 60...
21(chain B and (resid 1 through 61 or (resid 62...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERILEILE(chain A and (resid 1 through 59 or (resid 60...AA1 - 591 - 59
12ARGARGARGARG(chain A and (resid 1 through 59 or (resid 60...AA6060
13SERSERVALVAL(chain A and (resid 1 through 59 or (resid 60...AA1 - 3031 - 303
14SERSERVALVAL(chain A and (resid 1 through 59 or (resid 60...AA1 - 3031 - 303
15SERSERVALVAL(chain A and (resid 1 through 59 or (resid 60...AA1 - 3031 - 303
16SERSERVALVAL(chain A and (resid 1 through 59 or (resid 60...AA1 - 3031 - 303
21SERSERLYSLYS(chain B and (resid 1 through 61 or (resid 62...BB1 - 611 - 61
22SERSERSERSER(chain B and (resid 1 through 61 or (resid 62...BB6262
23SERSERVALVAL(chain B and (resid 1 through 61 or (resid 62...BB1 - 3031 - 303
24SERSERVALVAL(chain B and (resid 1 through 61 or (resid 62...BB1 - 3031 - 303
25SERSERVALVAL(chain B and (resid 1 through 61 or (resid 62...BB1 - 3031 - 303
26SERSERVALVAL(chain B and (resid 1 through 61 or (resid 62...BB1 - 3031 - 303

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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-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-TKX / 5-bromo-3-[(4-chloro-3-nitrophenyl)methoxy]pyridine-2-carbaldehyde


Mass: 371.571 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H8BrClN2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
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: 2.02 Å3/Da / Density % sol: 39.21 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MES pH 6.5, 20% PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 28, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.17→39.01 Å / Num. obs: 28447 / % possible obs: 98.6 % / Redundancy: 6.9 % / Biso Wilson estimate: 40.54 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.163 / Rpim(I) all: 0.067 / Rrim(I) all: 0.177 / Net I/σ(I): 8.5 / Num. measured all: 195718
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.17-2.246.92.2871712424950.3270.9312.4730.998.6
8.95-39.016.40.03227104250.9990.0140.03530.296.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.11.1_2575refinement
XDSdata reduction
Aimless0.5.32data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7NG3

7ng3


Resolution: 2.17→38.729 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2764 1341 4.72 %
Rwork0.2212 27053 -
obs0.2236 28394 98.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 118.61 Å2 / Biso mean: 48.6167 Å2 / Biso min: 24.23 Å2
Refinement stepCycle: final / Resolution: 2.17→38.729 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4492 0 42 31 4565
Biso mean--99.97 46.39 -
Num. residues----597
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044696
X-RAY DIFFRACTIONf_angle_d0.826402
X-RAY DIFFRACTIONf_chiral_restr0.05731
X-RAY DIFFRACTIONf_plane_restr0.004833
X-RAY DIFFRACTIONf_dihedral_angle_d3.633706
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2650X-RAY DIFFRACTION9.689TORSIONAL
12B2650X-RAY DIFFRACTION9.689TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.1701-2.24770.33471430.3271270198
2.2477-2.33760.34251390.3174265497
2.3376-2.4440.37761410.3083268399
2.444-2.57280.33861410.2889268498
2.5728-2.7340.31151470.276266198
2.734-2.9450.29411140.2579270398
2.945-3.24130.27551530.2405270899
3.2413-3.710.26741340.2139271298
3.71-4.67290.23991220.1676274699
4.6729-38.7290.22041070.1766280197
Refinement TLS params.Method: refined / Origin x: -16.8244 Å / Origin y: 12.6629 Å / Origin z: -28.2218 Å
111213212223313233
T0.2766 Å20.0486 Å20.041 Å2-0.3197 Å20.0165 Å2--0.3309 Å2
L0.2831 °2-0.2916 °20.4776 °2-0.6951 °2-0.1885 °2--1.309 °2
S0.0653 Å °0.0914 Å °0.0224 Å °-0.1284 Å °-0.0721 Å °-0.0877 Å °0.0044 Å °0.0882 Å °0.0016 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 308
2X-RAY DIFFRACTION1allB1 - 308
3X-RAY DIFFRACTION1allC1 - 36

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