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- PDB-7nf5: Crystal structure of MG-132 covalently bound to the main protease... -

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Entry
Database: PDB / ID: 7nf5
TitleCrystal structure of MG-132 covalently bound to the main protease (3CLpro/Mpro) of SARS-CoV-2 in spacegroup C2.
Components3C-like proteinase
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Mpro / 3CLpro / EXSCALATE4COV / drug discovery / Elettra / MG-132
Function / homology
Function and homology information


Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / Lyases; Phosphorus-oxygen lyases / modulation by virus of host autophagy ...Maturation of replicase proteins / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-2 sgRNAs / host cell endosome / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Translation of Replicase and Assembly of the Replication Transcription Complex / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / 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 protease activity / host cell Golgi apparatus / Replication of the SARS-CoV-2 genome / suppression by virus of host type I interferon production / host cell endoplasmic reticulum / SARS coronavirus main proteinase / induction by virus of catabolism of host mRNA / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / G-quadruplex RNA binding / host cell endoplasmic reticulum-Golgi intermediate compartment / suppression by virus of host ISG15-protein conjugation / protein K48-linked deubiquitination / suppression by virus of host toll-like receptor signaling pathway / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / transcription, RNA-templated / suppression by virus of host NF-kappaB cascade / viral transcription / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / methyltransferase cap1 / positive stranded viral RNA replication / protein autoprocessing / cysteine-type peptidase activity / viral genome replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / suppression by virus of host TRAF activity / helicase activity / ubiquitinyl hydrolase 1 / DNA helicase / thiol-dependent deubiquitinase / DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / RNA helicase / induction by virus of host autophagy / endonuclease activity / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / suppression by virus of host type I interferon-mediated signaling pathway / transcription, DNA-templated / host cell cytoplasm / protein dimerization 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 / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / 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 / Non-structural protein NSP16, coronavirus-like / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, middle domain superfamily / RNA polymerase, N-terminal, coronavirus / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Non-structural protein 14, coronavirus / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Sarbecovirus Nsp3c-N domain profile. / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Non-structural protein NSP3, N-terminal, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP1, 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 / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein 6, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3A domain-like superfamily / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Papain-like protease, N-terminal domain superfamily, coronavirus / Lipocalin signature. / Papain-like viral protease, palm and finger domains, coronavirus / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal 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. / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Coronavirus endopeptidase C30 / Non-structural protein NSP8, coronavirus-like / RNA synthesis protein NSP10, coronavirus / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP6 / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Peptidase C30, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Peptidase C16, coronavirus / Peptidase C30, domain 3, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus
Similarity search - Domain/homology
PHQ-Leu-Leu-Leu-aldehyde MG-132, bound form / Chem-ALD / ISOPROPYL ALCOHOL / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsCostanzi, E. / Demitri, N. / Giabbai, B. / Storici, P.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Commission101003551European Union
CitationJournal: Int J Mol Sci / Year: 2021
Title: Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L.
Authors: Costanzi, E. / Kuzikov, M. / Esposito, F. / Albani, S. / Demitri, N. / Giabbai, B. / Camasta, M. / Tramontano, E. / Rossetti, G. / Zaliani, A. / Storici, P.
History
DepositionFeb 5, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: citation / citation_author ...citation / citation_author / database_2 / entity / entity_name_com / entity_src_gen / pdbx_database_proc / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _entity.pdbx_ec / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _struct.pdbx_center_of_mass_x / _struct.pdbx_center_of_mass_y / _struct.pdbx_center_of_mass_z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,82612
Polymers33,8261
Non-polymers1,00011
Water2,342130
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,65124
Polymers67,6512
Non-polymers2,00022
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area8360 Å2
ΔGint-23 kcal/mol
Surface area24940 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)110.017, 55.078, 47.525
Angle α, β, γ (deg.)90.000, 101.231, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-409-

CL

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 3C-like proteinase / 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
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase

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Non-polymers , 6 types, 141 molecules

#2: Chemical ChemComp-ALD / N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-L-leucinamide


Type: Peptide-like / Class: Inhibitor / Mass: 477.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H43N3O5 / Feature type: SUBJECT OF INVESTIGATION / References: PHQ-Leu-Leu-Leu-aldehyde MG-132, bound form
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.09 Å3/Da / Density % sol: 41.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.05M Magnesium chloride hexahydrate , 0.1M MES pH 6.5, 5 % w/vPEG 4000, 10% v/v 2-Propanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.94→53.96 Å / Num. obs: 20793 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 27.93 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.146 / Net I/σ(I): 8
Reflection shellResolution: 1.94→1.99 Å / Num. unique obs: 1422 / CC1/2: 0.637

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7ALH
Resolution: 1.94→49.06 Å / SU ML: 0.2475 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.3396
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2246 1033 4.97 %
Rwork0.1819 19748 -
obs0.184 20781 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.25 Å2
Refinement stepCycle: LAST / Resolution: 1.94→49.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 65 130 2553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01322477
X-RAY DIFFRACTIONf_angle_d1.07083356
X-RAY DIFFRACTIONf_chiral_restr0.0666378
X-RAY DIFFRACTIONf_plane_restr0.0092433
X-RAY DIFFRACTIONf_dihedral_angle_d14.3804888
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.94-2.040.29871400.24862805X-RAY DIFFRACTION100
2.04-2.170.27021470.22622805X-RAY DIFFRACTION99.93
2.17-2.340.27381400.21012818X-RAY DIFFRACTION99.83
2.34-2.570.24411810.19382761X-RAY DIFFRACTION99.97
2.57-2.950.22991560.18612823X-RAY DIFFRACTION99.87
2.95-3.710.21571320.16962846X-RAY DIFFRACTION100
3.71-49.060.18911370.162890X-RAY DIFFRACTION99.67
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.007352289441.00404091841.520455557082.735303589321.577846699152.830375798530.3346519405150.0714118499742-0.298179044760.0962653779213-0.0304836899276-0.04442634391310.843312523232-0.265739182467-0.1651038953120.385744960401-0.0570065264969-0.0630419502550.2142961121650.01042305461710.256334658525-15.3863760154-39.07117130338.34802280012
20.697235196390.213781500110.5170213606311.836846484652.835587799084.385153894060.0692490533742-0.0200835694617-0.0264053293422-0.0133736638991-0.1513384750910.110090249310.0387206691365-0.427689686210.03699300420290.170783430994-0.01548159935430.01562848529930.2000304727680.01820672679690.20733843275-16.4076284122-24.515019869915.307678515
33.17463510403-0.63426816294-0.285998139453.4962141638-0.6715076786634.334461305090.0125431824904-0.1128534249610.239266057690.09388328376330.2059923920780.014899407806-0.261922610524-0.197006019478-0.1994893724890.1564996953380.02172228176230.02650835517170.240633181497-0.00742113700670.161726603444-18.0098677674-10.734444799632.6529441826
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 120 )1 - 1201 - 120
22chain 'A' and (resid 121 through 213 )121 - 213121 - 213
33chain 'A' and (resid 214 through 305 )214 - 305214 - 305

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