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- PDB-7tiu: Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB46 -

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Entry
Database: PDB / ID: 7tiu
TitleCrystal structure of SARS-CoV-2 3CL in complex with inhibitor EB46
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / VIRAL PROTEIN / 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 / omega peptidase activity / 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 / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / 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 / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / lipid binding / 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 / 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 / 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 replicase NSP7 / Peptidase family C16 domain profile. / 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. / 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
PHOSPHATE ION / Chem-V46 / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsForouhar, F. / Liu, H. / Iketani, S. / Zack, A. / Khanizeman, N. / Bednarova, E. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. ...Forouhar, F. / Liu, H. / Iketani, S. / Zack, A. / Khanizeman, N. / Bednarova, E. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, S.J. / Quinn, C. / Li, W. / Shion, H. / Jurtschenko, C. / Lauber, M.A. / McDonald, T. / Stokes, M.E. / Hurst, B. / Rovis, T. / Chavez, A. / Ho, D.D. / Stockwell, B.R.
Funding support United States, 7items
OrganizationGrant numberCountry
Jack Ma Foundation United States
Burroughs Wellcome Fund
Columbia Technology Ventures
Columbia Translational Therapeutics (TRx)
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)T32AI106711
National Science Foundation (NSF, United States)2029943
Department of Energy (DOE, United States)DE-AC02-06CH11357
CitationJournal: Nat Commun / Year: 2022
Title: Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.
Authors: Liu, H. / Iketani, S. / Zask, A. / Khanizeman, N. / Bednarova, E. / Forouhar, F. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, ...Authors: Liu, H. / Iketani, S. / Zask, A. / Khanizeman, N. / Bednarova, E. / Forouhar, F. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, S.J. / Quinn, C. / Li, W. / Shion, H. / Xia, X. / Daniels, J.D. / Bartolo-Cruz, M. / Farina, M. / Rajbhandari, P. / Jurtschenko, C. / Lauber, M.A. / McDonald, T. / Stokes, M.E. / Hurst, B.L. / Rovis, T. / Chavez, A. / Ho, D.D. / Stockwell, B.R.
History
DepositionJan 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 13, 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

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4654
Polymers33,8261
Non-polymers6393
Water3,441191
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,9308
Polymers67,6512
Non-polymers1,2796
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3360 Å2
ΔGint-50 kcal/mol
Surface area25540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.230, 81.014, 54.507
Angle α, β, γ (deg.)90.000, 116.440, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-402-

PO4

21A-402-

PO4

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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 (E. coli)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-V46 / (1S,2S)-2-[(N-{[(3-chlorophenyl)methoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 519.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30ClN3O8S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.84 Å3/Da / Density % sol: 56.71 % / Description: block-shaped
Crystal growTemperature: 277 K / Method: microbatch / pH: 5
Details: 0.1 M potassium thiocyanate, 0.1 M sodium acetate, pH 5, and 20% (w/v) PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.56→48.81 Å / Num. obs: 53155 / % possible obs: 98.2 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.043 / Net I/σ(I): 17.6
Reflection shellResolution: 1.56→1.58 Å / Redundancy: 4.8 % / Rmerge(I) obs: 1.156 / Num. unique obs: 2231 / CC1/2: 0.741 / % possible all: 83.2

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JSU

7jsu


Resolution: 1.65→48.81 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.4 / Phase error: 23.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1957 4487 9.97 %
Rwork0.1681 40525 -
obs0.1708 45012 98.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 172.48 Å2 / Biso mean: 47.3306 Å2 / Biso min: 21.51 Å2
Refinement stepCycle: final / Resolution: 1.65→48.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2329 0 36 193 2558
Biso mean--53.03 53.38 -
Num. residues----301
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.65-1.670.31731620.27931330149299
1.67-1.690.25161550.24191339149499
1.69-1.710.24811530.22881342149598
1.71-1.730.25091260.21811339146598
1.73-1.750.28071550.22221359151499
1.75-1.780.23421600.20851304146499
1.78-1.80.22291510.196113741525100
1.8-1.830.24011660.1891331149799
1.83-1.860.24541560.18761347150399
1.86-1.890.26231420.19411360150299
1.89-1.920.30631390.2091362150199
1.92-1.960.24211270.19051369149699
1.96-1.990.2181390.18311341148098
1.99-2.030.221580.18051318147698
2.03-2.080.23851430.179313741517100
2.08-2.130.22191490.18211339148899
2.13-2.180.22031780.16991340151899
2.18-2.240.20911410.1721343148499
2.24-2.310.21231800.18371329150999
2.31-2.380.22871660.18421344151099
2.38-2.460.19431440.17951344148899
2.46-2.560.22851340.19213991533100
2.56-2.680.20631360.18711339147599
2.68-2.820.20241510.1881328147997
2.82-30.2231280.18611379150798
3-3.230.21471480.18251371151999
3.23-3.550.18021490.18181347149699
3.55-4.070.15471620.14651365152799
4.07-5.120.16161420.12551386152899
5.13-48.810.16791470.14471383153098
Refinement TLS params.Method: refined / Origin x: -5.4619 Å / Origin y: -1.2824 Å / Origin z: 12.1199 Å
111213212223313233
T0.2254 Å2-0.0301 Å2-0.0097 Å2-0.254 Å2-0.019 Å2--0.2678 Å2
L0.6956 °20.1808 °2-0.5369 °2-0.972 °20.4783 °2--2.4522 °2
S0.0627 Å °-0.0507 Å °-0.0604 Å °0.0275 Å °-0.0234 Å °-0.0783 Å °-0.099 Å °-0.0811 Å °0.0191 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 301
2X-RAY DIFFRACTION1allA401 - 403
3X-RAY DIFFRACTION1allS1 - 193

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