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- PDB-1p9u: Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design ... -

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Basic information

Entry
Database: PDB / ID: 1p9u
TitleCoronavirus Main Proteinase (3CLpro) Structure: Basis for Design of anti-SARS Drugs
Components
  • PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR
  • putative coronavirus nsp2 (3CL-PRO)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SARS-COV / HCOV / TGEV / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


RNA exonuclease activity / host cell membrane / DNA helicase activity / viral genome replication / methyltransferase activity / Lyases; Phosphorus-oxygen lyases / methylation / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-RNA exonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment ...RNA exonuclease activity / host cell membrane / DNA helicase activity / viral genome replication / methyltransferase activity / Lyases; Phosphorus-oxygen lyases / methylation / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-RNA exonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / mRNA guanylyltransferase / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / mRNA (nucleoside-2'-O-)-methyltransferase activity / endonuclease activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / DNA helicase / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / membrane => GO:0016020 / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Alphacoronavirus nsp1 / Replicase polyprotein N-term from Coronavirus nsp1 / Alphacoronavirus nsp1 domain superfamily / : / Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain ...Alphacoronavirus nsp1 / Replicase polyprotein N-term from Coronavirus nsp1 / Alphacoronavirus nsp1 domain superfamily / : / Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2-O-methyltransferase / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 13, 1B domain, coronavirus / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) 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 / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Coronavirus 3Ecto domain profile. / Papain-like protease, N-terminal domain superfamily, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus
Similarity search - Domain/homology
INHIBITOR CH2-QLTSNV-Z (SUBSTRATE-ANALOG) / Replicase polyprotein 1ab / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesTransmissible gastroenteritis virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsAnand, K. / Ziebuhr, J. / Wadhwani, P. / Mesters, J.R. / Hilgenfeld, R.
CitationJournal: Science / Year: 2003
Title: Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of anti-SARS Drugs
Authors: Anand, K. / Ziebuhr, J. / Wadhwani, P. / Mesters, J.R. / Hilgenfeld, R.
History
DepositionMay 12, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: putative coronavirus nsp2 (3CL-PRO)
B: putative coronavirus nsp2 (3CL-PRO)
C: putative coronavirus nsp2 (3CL-PRO)
D: putative coronavirus nsp2 (3CL-PRO)
E: putative coronavirus nsp2 (3CL-PRO)
F: putative coronavirus nsp2 (3CL-PRO)
G: PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR
H: PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,21036
Polymers200,4328
Non-polymers2,77828
Water16,646924
1
A: putative coronavirus nsp2 (3CL-PRO)
B: putative coronavirus nsp2 (3CL-PRO)
G: PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,88311
Polymers67,0933
Non-polymers7918
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5220 Å2
ΔGint-101 kcal/mol
Surface area25700 Å2
MethodPISA
2
C: putative coronavirus nsp2 (3CL-PRO)
D: putative coronavirus nsp2 (3CL-PRO)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,34813
Polymers66,2472
Non-polymers1,10111
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 Å2
ΔGint-129 kcal/mol
Surface area26140 Å2
MethodPISA
3
E: putative coronavirus nsp2 (3CL-PRO)
F: putative coronavirus nsp2 (3CL-PRO)
H: PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,97912
Polymers67,0933
Non-polymers8879
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5190 Å2
ΔGint-128 kcal/mol
Surface area25620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.390, 158.550, 88.200
Angle α, β, γ (deg.)90.00, 94.40, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
putative coronavirus nsp2 (3CL-PRO)


Mass: 33123.398 Da / Num. of mol.: 6 / Fragment: TGEV main proteinase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Transmissible gastroenteritis virus / Genus: Coronavirus / Gene: ORF1a / Plasmid details: derivative of pMal-c2 / Plasmid: pMal-Mpro / Production host: Escherichia coli (E. coli) / Strain (production host): TB1 / References: UniProt: Q9IW06, UniProt: P0C6Y5*PLUS
#2: Protein/peptide PHQ-VNSTLQ-CHLOROMETHYLKETONE INHIBITOR


Type: Peptide-like / Class: Inhibitor / Mass: 845.768 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: substrate-analog / References: INHIBITOR CH2-QLTSNV-Z (SUBSTRATE-ANALOG)
#3: Chemical...
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-MRD / (4R)-2-METHYLPENTANE-2,4-DIOL / 2-Methyl-2,4-pentanediol


Mass: 118.174 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 924 / Source method: isolated from a natural source / Formula: H2O

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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: 2.52 Å3/Da / Density % sol: 51.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: Ammonium Sulfate, MPD, DDT, Dioxane, HEPES, pH 8.8, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, Hamburg / Beamline: X13 / Wavelength: 0.802 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 1, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.802 Å / Relative weight: 1
ReflectionResolution: 2.37→39.64 Å / Num. all: 79097 / Num. obs: 78630 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 36.9 Å2 / Rmerge(I) obs: 0.058
Reflection shellResolution: 2.37→2.41 Å / % possible all: 98.2
Reflection
*PLUS
Lowest resolution: 50 Å / Num. obs: 79667 / % possible obs: 99.8 % / Redundancy: 7.1 % / Num. measured all: 569126 / Rmerge(I) obs: 0.08
Reflection shell
*PLUS
Rmerge(I) obs: 0.28

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Processing

Software
NameVersionClassification
CNS1.1refinement
MAR345data collection
SCALEPACKdata scaling
CNS1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.37→39.64 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 600772.91 / Data cutoff high rms absF: 600772.91 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.234 2401 3 %RANDOM
Rwork0.191 ---
all0.2 79097 --
obs0.2 78630 98.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.6391 Å2 / ksol: 0.34457 e/Å3
Displacement parametersBiso mean: 42.7 Å2
Baniso -1Baniso -2Baniso -3
1-4.82 Å20 Å24.03 Å2
2--0.18 Å20 Å2
3----4.99 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.33 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.34 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.37→39.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13905 0 152 924 14981
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.73
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 2.37→2.52 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.306 382 3 %
Rwork0.232 12449 -
obs--96.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2PROTEIN-CYO-CTK-CMK.PARAMPROTEIN-CYO-CTK-CMK.TOP
X-RAY DIFFRACTION3WATER_REP.PARAM
X-RAY DIFFRACTION4ION.PARAM
X-RAY DIFFRACTION5LIGAND-MPD-DIOXANE.PARAM
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg24.9
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.73

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