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- PDB-7c6s: Crystal structure of the SARS-CoV-2 main protease complexed with ... -

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Basic information

Entry
Database: PDB / ID: 7c6s
TitleCrystal structure of the SARS-CoV-2 main protease complexed with Boceprevir
Components3C-like proteinase
KeywordsVIRAL PROTEIN / SARS-CoV-2 / 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
boceprevir (bound form) / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsFu, L. / Feng, Y.
CitationJournal: Nat Commun / Year: 2020
Title: Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease.
Authors: Fu, L. / Ye, F. / Feng, Y. / Yu, F. / Wang, Q. / Wu, Y. / Zhao, C. / Sun, H. / Huang, B. / Niu, P. / Song, H. / Shi, Y. / Li, X. / Tan, W. / Qi, J. / Gao, G.F.
History
DepositionMay 22, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Derived calculations / Category: citation / citation_author / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _struct_conn.pdbx_leaving_atom_flag
Revision 1.2Mar 10, 2021Group: Structure summary / Category: entity_name_com

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3472
Polymers33,8261
Non-polymers5221
Water5,621312
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6944
Polymers67,6512
Non-polymers1,0432
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2680 Å2
ΔGint-9 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.230, 80.245, 54.484
Angle α, β, γ (deg.)90.000, 116.717, 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-527-

HOH

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Components

#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 K-12 (bacteria) / Strain (production host): K-12
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-U5G / boceprevir (bound form) / (1R,2S,5S)-N-[(2S,3R)-4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl]-3-[N-(tert-butylcarbamoyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide


Mass: 521.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H47N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 312 / Source method: isolated from a natural source / Formula: H2O
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: 2.81 Å3/Da / Density % sol: 56.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 20% PEG5000,0.1 M BIS-TRIS

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 49018 / % possible obs: 99.9 % / Redundancy: 7.5 % / Biso Wilson estimate: 12.57 Å2 / CC1/2: 0.998 / Net I/σ(I): 22.3
Reflection shellResolution: 1.6→1.66 Å / Num. unique obs: 4873 / CC1/2: 0.897

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BRP
Resolution: 1.6→48.67 Å / SU ML: 0.1781 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 23.2153
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2222 2251 4.96 %
Rwork0.2075 43100 -
obs0.2082 45351 92.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.71 Å2
Refinement stepCycle: LAST / Resolution: 1.6→48.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2323 0 37 312 2672
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062436
X-RAY DIFFRACTIONf_angle_d0.75783327
X-RAY DIFFRACTIONf_chiral_restr0.0539380
X-RAY DIFFRACTIONf_plane_restr0.005430
X-RAY DIFFRACTIONf_dihedral_angle_d21.4311886
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.3117790.28281333X-RAY DIFFRACTION46.94
1.64-1.680.325890.27441825X-RAY DIFFRACTION62.32
1.68-1.720.2951100.26572367X-RAY DIFFRACTION81.29
1.72-1.760.2811450.26422688X-RAY DIFFRACTION92.52
1.76-1.820.27221580.24382832X-RAY DIFFRACTION97.68
1.82-1.870.26371580.22822888X-RAY DIFFRACTION99.54
1.87-1.940.2531720.22512887X-RAY DIFFRACTION100
1.94-2.020.23781450.22172920X-RAY DIFFRACTION100
2.02-2.110.22841410.22132923X-RAY DIFFRACTION99.97
2.11-2.220.22461540.21082845X-RAY DIFFRACTION99.37
2.22-2.360.20731530.21132938X-RAY DIFFRACTION100
2.36-2.540.22811440.2242907X-RAY DIFFRACTION99.97
2.54-2.80.24651660.21392897X-RAY DIFFRACTION99.64
2.8-3.20.22611480.20142945X-RAY DIFFRACTION100
3.2-4.040.17651410.18172930X-RAY DIFFRACTION99.71
4.04-48.670.1711480.16222975X-RAY DIFFRACTION99.59
Refinement TLS params.Method: refined / Origin x: -6.58958195121 Å / Origin y: -27.0775482675 Å / Origin z: 12.0433003178 Å
111213212223313233
T0.0429840270199 Å20.0274279194597 Å20.000274830654006 Å2-0.0631132985203 Å20.0170036528076 Å2--0.0592508469162 Å2
L0.719905202027 °2-0.184805602787 °2-0.468271113658 °2-0.894788674412 °2-0.183870048582 °2--1.21572239936 °2
S-0.017482131681 Å °0.0184581056231 Å °-0.0344502858022 Å °0.0117683255049 Å °0.0188809020549 Å °0.0748476877487 Å °-0.0605850850847 Å °0.0683902848125 Å °-0.00144183795536 Å °
Refinement TLS groupSelection details: all

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