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- PDB-4zro: 2.1 A X-Ray Structure of FIPV-3CLpro bound to covalent inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zro
Title2.1 A X-Ray Structure of FIPV-3CLpro bound to covalent inhibitor
Components
  • 3C-like proteinase
  • Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
KeywordsHydrolase/Hydrolase Inhibitor / Coronavirus / main protease / 3CLpro / Mpro / FIPV / FCoV / inhibitor complex / feline infectious peritonitis / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 5'-3' DNA helicase activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / mRNA guanylyltransferase / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity ...host cell membrane / viral genome replication / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 5'-3' DNA helicase activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 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 / endonuclease activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / DNA helicase / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / 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 / virus-mediated perturbation of host defense response / 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. / Papain-like protease, N-terminal domain superfamily, coronavirus / : / Coronavirus 3Ecto domain profile. / Trypsin-like serine proteases / : / 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
Similarity search - Domain/homology
Bound inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesFeline coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.0566 Å
AuthorsSt John, S.E. / Mesecar, A.D.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI085089 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI26603 United States
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design.
Authors: St John, S.E. / Therkelsen, M.D. / Nyalapatla, P.R. / Osswald, H.L. / Ghosh, A.K. / Mesecar, A.D.
History
DepositionMay 12, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2015Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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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
C: 3C-like proteinase
D: 3C-like proteinase
E: Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
F: Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
G: Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
H: Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,58810
Polymers133,4318
Non-polymers1562
Water9,854547
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)100.449, 101.896, 110.158
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
3C-like proteinase / 3CL-PRO / 3CLp / M-PRO / nsp5


Mass: 32730.045 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Feline coronavirus (strain FIPV WSU-79/1146)
Strain: FIPV WSU-79/1146 / Gene: rep, 1a-1b / Production host: Escherichia coli (E. coli)
References: UniProt: Q98VG9, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide
Bounded inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide


Type: Peptide-like / Class: Inhibitor / Mass: 627.770 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
References: Bound inhibitor of N-(tert-butoxycarbonyl)-L-seryl-L-valyl-N-{(2S)-5-ethoxy-5-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]pentan-2-yl}-L-leucinamide
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 547 / 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: 2.15 Å3/Da / Density % sol: 42.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.05 M LiCl, 0.1 M Tris pH 8.5, 32% PEG-4000, cryo-protected with 15% MPD

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.0566→50 Å / Num. obs: 70555 / % possible obs: 100 % / Redundancy: 7.9 % / Biso Wilson estimate: 31.57 Å2 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.04 / Rrim(I) all: 0.112 / Χ2: 1.727 / Net I/av σ(I): 27.767 / Net I/σ(I): 8.4 / Num. measured all: 525235
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.147.80.76132820.8680.2880.8140.93999.9
2.14-2.187.90.66932770.8920.2530.7160.97599.9
2.18-2.227.80.56932730.9150.2150.6090.98199.9
2.22-2.267.90.51833020.9280.1960.5541.00199.9
2.26-2.317.90.45432820.9530.1710.4850.98999.9
2.31-2.377.90.39832940.9570.150.4261.019100
2.37-2.427.90.34432970.9650.130.3681.04399.9
2.42-2.497.90.30332910.9720.1140.3241.089100
2.49-2.567.90.25833110.9780.0970.2761.153100
2.56-2.6580.21433020.9850.080.2291.221100
2.65-2.7480.19333160.9880.0720.2061.287100
2.74-2.8580.16233100.9910.0610.1731.368100
2.85-2.988.10.13733460.9930.0510.1461.582100
2.98-3.148.10.11933050.9940.0440.1271.842100
3.14-3.338.10.10633500.9940.040.1142.32100
3.33-3.5980.09333310.9960.0350.12.905100
3.59-3.957.90.07433640.9970.0280.0793.24100
3.95-4.527.80.06233740.9980.0230.0663.375100
4.52-5.77.70.05634310.9980.0210.063.162100
5.7-507.20.05135750.9980.020.0542.91299.8

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Processing

Software
NameVersionClassification
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHENIXphasing
RefinementResolution: 2.0566→43.641 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2309 1996 2.83 %
Rwork0.1704 68559 -
obs0.1721 70555 99.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 130.01 Å2 / Biso mean: 37.1665 Å2 / Biso min: 11.6 Å2
Refinement stepCycle: final / Resolution: 2.0566→43.641 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9175 0 184 547 9906
Biso mean--39.87 40.57 -
Num. residues----1196
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089578
X-RAY DIFFRACTIONf_angle_d1.17612982
X-RAY DIFFRACTIONf_chiral_restr0.0431434
X-RAY DIFFRACTIONf_plane_restr0.0051677
X-RAY DIFFRACTIONf_dihedral_angle_d15.0643395
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0566-2.1080.32221370.23894598473595
2.108-2.1650.2761380.236448665004100
2.165-2.22870.33171440.217848595003100
2.2287-2.30060.28541400.215848354975100
2.3006-2.38290.29111450.208748855030100
2.3829-2.47830.27411340.20148644998100
2.4783-2.5910.27021410.193248735014100
2.591-2.72760.28531440.191449005044100
2.7276-2.89850.29051410.195649055046100
2.8985-3.12220.25131430.195349105053100
3.1222-3.43630.25361440.181749175061100
3.4363-3.93330.20921460.154249675113100
3.9333-4.95440.17781480.125149995147100
4.9544-43.65120.16181510.136451815332100
Refinement TLS params.Method: refined / Origin x: 24.3898 Å / Origin y: 7.2319 Å / Origin z: 24.5606 Å
111213212223313233
T0.145 Å2-0.0023 Å2-0.0028 Å2-0.1482 Å20.0059 Å2--0.136 Å2
L0.122 °2-0.004 °2-0.0046 °2-0.1197 °20.0613 °2--0.0332 °2
S-0.0112 Å °0.0001 Å °0.0016 Å °0.0015 Å °0.0162 Å °-0.0009 Å °-0.0154 Å °-0.0263 Å °-0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 299
2X-RAY DIFFRACTION1allB1 - 299
3X-RAY DIFFRACTION1allC1 - 299
4X-RAY DIFFRACTION1allD1 - 299
5X-RAY DIFFRACTION1allJ1 - 584
6X-RAY DIFFRACTION1all3
7X-RAY DIFFRACTION1all1
8X-RAY DIFFRACTION1all2
9X-RAY DIFFRACTION1all4
10X-RAY DIFFRACTION1allE1
11X-RAY DIFFRACTION1allE2

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