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- PDB-7ca8: The crystal structure of COVID-19 main protease in complex with a... -

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Basic information

Entry
Database: PDB / ID: 7ca8
TitleThe crystal structure of COVID-19 main protease in complex with an inhibitor Shikonin
Components3C-like proteinase
KeywordsVIRAL PROTEIN / Main Protease / inhibitor
Function / homology
Function and homology information


Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / viral RNA-directed RNA polymerase complex / exoribonuclease complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex ...Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / viral RNA-directed RNA polymerase complex / exoribonuclease complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex / RNA phosphodiester bond hydrolysis, exonucleolytic / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / positive regulation of RNA biosynthetic process / Lyases; Phosphorus-oxygen lyases / modulation by virus of host autophagy / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific peptidase activity / SARS coronavirus main proteinase / suppression by virus of host type I interferon production / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endosome / 3'-5'-exoribonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / induction by virus of catabolism of host mRNA / cytoplasmic viral factory / protein K48-linked deubiquitination / G-quadruplex RNA binding / suppression by virus of host ISG15-protein conjugation / 7-methylguanosine mRNA capping / transcription, RNA-templated / viral transcription / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / suppression by virus of host toll-like receptor signaling pathway / host cell Golgi apparatus / host cell endoplasmic reticulum / suppression by virus of host NF-kappaB cascade / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / methyltransferase cap1 / positive regulation of viral genome replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / positive stranded viral RNA replication / suppression by virus of host TRAF activity / protein autoprocessing / cysteine-type peptidase activity / helicase activity / ubiquitinyl hydrolase 1 / DNA helicase / DNA helicase activity / cysteine-type deubiquitinase activity / single-stranded RNA binding / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / protein processing / host cell perinuclear region of cytoplasm / viral protein processing / RNA helicase / lyase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / suppression by virus of host gene expression / endonuclease activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / transcription, DNA-templated / suppression by virus of host type I interferon-mediated signaling pathway / host cell cytoplasm / protein dimerization activity / host cell nucleus / ATP hydrolysis activity / protein homodimerization activity / zinc ion binding / integral component of membrane / ATP binding / identical protein binding / cytosol
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 14, betacoronavirus / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Viral (Superfamily 1) RNA helicase / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus proofreading exoribonuclease / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP16, coronavirus-like / Coronavirus RNA-dependent RNA polymerase, N-terminal / Non-structural protein 14, coronavirus / Nonstructural protein 15, middle domain, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerisation / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein NSP3, N-terminal, betacoronavirus / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Lipocalin signature. / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP1, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Non-structural protein 6, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3d Ubl domain profile. / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Non-structural protein NSP7, coronavirus / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP8 / Coronavirus endopeptidase C30 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP3, C-terminal / Coronavirus papain-like peptidase / Coronavirus replicase NSP4, N-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Non-structural protein NSP7 superfamily, coronavirus / Coronavirus replicase NSP3, C-terminal / Peptidase C30, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP8, coronavirus / Non-structural protein 6, coronavirus
Similarity search - Domain/homology
Chem-FNO / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsZhou, X.L. / Zhong, F.L. / Lin, C. / Li, J. / Zhang, J.
CitationJournal: Sci Bull (Beijing) / Year: 2021
Title: Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode.
Authors: Li, J. / Zhou, X. / Zhang, Y. / Zhong, F. / Lin, C. / McCormick, P.J. / Jiang, F. / Luo, J. / Zhou, H. / Wang, Q. / Fu, Y. / Duan, J. / Zhang, J.
History
DepositionJun 8, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 14, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)66,2383
Polymers65,9492
Non-polymers2881
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-9 kcal/mol
Surface area24620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.960, 102.370, 103.540
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein 3C-like proteinase / pp1ab / ORF1ab polyprotein


Mass: 32974.613 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) / Strain (production host): BL21(DE3)
References: UniProt: P0DTD1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, SARS coronavirus main proteinase, RNA-directed RNA polymerase, DNA ...References: UniProt: P0DTD1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases, SARS coronavirus main proteinase, RNA-directed RNA polymerase, DNA helicase, RNA helicase, Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters, Hydrolases; Acting on ester bonds, Transferases; Transferring one-carbon groups; Methyltransferases
#2: Chemical ChemComp-FNO / 2-[(1R)-4-methyl-1-oxidanyl-pent-3-enyl]-5,8-bis(oxidanyl)naphthalene-1,4-dione / shikonin / Alkannin


Mass: 288.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.76 Å3/Da / Density % sol: 55.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.1M HEPES 7.5, 20% PEG 10000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97913 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97913 Å / Relative weight: 1
ReflectionResolution: 2.45→56.8148268869 Å / Num. obs: 27221 / % possible obs: 99.7 % / Redundancy: 13.1 % / Biso Wilson estimate: 49.7260315794 Å2 / Rmerge(I) obs: 0.128 / Net I/σ(I): 15.7
Reflection shellResolution: 2.45→2.51 Å / Rmerge(I) obs: 1.568 / Num. unique obs: 2015

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PHENIX1.11.1_2575refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7C2Q
Resolution: 2.45→56.81 Å / SU ML: 0.38446878867 / Cross valid method: NONE / σ(F): 1.35012381842 / Phase error: 32.30147074
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.278864221627 3785 7.40023852816 %
Rwork0.229531125451 47362 -
obs0.233134579919 27158 99.6454246138 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.5092305882 Å2
Refinement stepCycle: LAST / Resolution: 2.45→56.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4188 0 21 41 4250
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812085352254305
X-RAY DIFFRACTIONf_angle_d1.019427274075878
X-RAY DIFFRACTIONf_chiral_restr0.0527643305271681
X-RAY DIFFRACTIONf_plane_restr0.00635264329791761
X-RAY DIFFRACTIONf_dihedral_angle_d18.42882221571453
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.4810.3636335965371460.3511380644271777X-RAY DIFFRACTION99.8961038961
2.481-2.51370.4610604091231340.3500771830151800X-RAY DIFFRACTION99.1286519733
2.5137-2.54810.4489748759471350.35334629941723X-RAY DIFFRACTION99.3582887701
2.5481-2.58450.4012985594971400.3300306746971745X-RAY DIFFRACTION99.6827075621
2.5845-2.62310.4195088958761360.3216024445791786X-RAY DIFFRACTION99.585492228
2.6231-2.66410.3394760530041320.316082087971714X-RAY DIFFRACTION99.7837837838
2.6641-2.70780.3220773664991340.305182162021767X-RAY DIFFRACTION99.4767137624
2.7078-2.75450.4049768781821460.2924493092061761X-RAY DIFFRACTION99.790685505
2.7545-2.80450.3759851763341400.2839319486281748X-RAY DIFFRACTION99.5780590717
2.8045-2.85850.3123748434711380.2732945366261765X-RAY DIFFRACTION99.8426023085
2.8585-2.91680.3541263626041390.2501919994741750X-RAY DIFFRACTION99.7886951928
2.9168-2.98020.2433169921661461741X-RAY DIFFRACTION99.3157894737
2.9802-3.04960.3191812456751340.2587963107051754X-RAY DIFFRACTION99.6832101373
3.0496-3.12580.2805163666181370.2431015752851746X-RAY DIFFRACTION99.7880233174
3.1258-3.21030.3266324543621380.2417645683511793X-RAY DIFFRACTION99.7932816537
3.2103-3.30480.2759869725671350.2371160060511730X-RAY DIFFRACTION99.7326203209
3.3048-3.41140.2733684914651480.2263184862581787X-RAY DIFFRACTION99.793708097
3.4114-3.53340.2885417319281290.222708625961730X-RAY DIFFRACTION99.5715050884
3.5334-3.67480.2685124824391410.233416832811726X-RAY DIFFRACTION99.5733333333
3.6748-3.8420.3135915389841490.2233487680951770X-RAY DIFFRACTION100
3.842-4.04450.2944319516591440.2012646801491759X-RAY DIFFRACTION99.8426023085
4.0445-4.29780.2306099903781450.1908899219851753X-RAY DIFFRACTION100
4.2978-4.62950.2497211715571380.1895400120771750X-RAY DIFFRACTION100
4.6295-5.09520.2114355290041470.1867529206931754X-RAY DIFFRACTION99.7376705142
5.0952-5.83180.2608281683731470.2169454169051756X-RAY DIFFRACTION99.9474789916
5.8318-7.3450.22500984131411759X-RAY DIFFRACTION99.8948475289
7.345-56.810.2329449193231460.1975053882991718X-RAY DIFFRACTION98.0536559705

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