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- PDB-7k6d: SARS-CoV-2 Main Protease Co-Crystal Structure with Telaprevir Det... -

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Basic information

Entry
Database: PDB / ID: 7k6d
TitleSARS-CoV-2 Main Protease Co-Crystal Structure with Telaprevir Determined from Crystals Grown with 40 nL Acoustically Ejected Mpro Droplets at 1.48 A Resolution (Cryo-protected)
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / SARS-CoV-2 / Main Protease / 3CLpro/Mpro / Telaprevir / Acoustic Drop Ejection / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / exoribonuclease complex / viral RNA-directed RNA polymerase complex / endoribonuclease complex / Transcription of SARS-CoV-2 sgRNAs / endopeptidase complex / 5'-3' RNA helicase activity / mRNA cap methyltransferase complex ...Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / exoribonuclease complex / viral RNA-directed RNA polymerase 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 / modulation by virus of host autophagy / Lyases; Phosphorus-oxygen lyases / 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 / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) 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 / Nonstructural protein 15, middle domain, coronavirus / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP15, middle domain superfamily / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus replicase NSP15, middle domain / Coronavirus 2'-O-methyltransferase / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / 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 NSP3, N-terminal, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP1 superfamily, betacoronavirus / Betacoronavirus replicase NSP3, N-terminal / Betacoronavirus SUD-C domain / (+) 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 / Betacoronavirus single-stranded poly(A) binding domain / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP1, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 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 / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3d Ubl domain profile. / 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 / Non-structural protein NSP7, coronavirus / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP8 / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus main protease (M-pro) domain profile. / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus replicase NSP6 / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein 6, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus
Similarity search - Domain/homology
TELAPREVIR, bound form / Chem-SV6 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsKreitler, D.F. / Andi, B. / Kumaran, D. / Soares, A.S. / Shi, W. / Jakoncic, J. / Fuchs, M.R. / Keereetaweep, J. / Shanklin, J. / McSweeney, S.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P30GM133893 United States
Department of Energy (DOE, United States)KP1605010 United States
Brookhaven National Laboratory (BNL)LDRD 20-042 United States
National Virtual Biotechnology Laboratory (NVBL)Coronavirus CARES Act United States
CitationJournal: To Be Published
Title: SARS-CoV-2 Main Protease Co-Crystal Structure with Telaprevir Determined from Crystals Grown with 40 nL Acoustically Ejected Mpro Droplets at 1.48 A Resolution (Cryo-protected)
Authors: Kreitler, D.F. / Andi, B. / Kumaran, D. / Soares, A.S. / Jakoncic, J. / Fuchs, M. / Keereetaweep, J. / Shanklin, J. / McSweeney, S.
History
DepositionSep 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Author supporting evidence / Structure summary / Category: pdbx_audit_support / pdbx_molecule_features / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 27, 2021Group: Structure summary / Category: entity / entity_name_com / Item: _entity.pdbx_ec / _entity_name_com.name
Revision 1.3Sep 1, 2021Group: Data collection / Database references / Category: database_2 / diffrn_detector
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_detector.type

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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)34,5863
Polymers33,8261
Non-polymers7602
Water1,06359
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1716
Polymers67,6512
Non-polymers1,5204
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3670 Å2
ΔGint-7 kcal/mol
Surface area24310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.760, 54.820, 48.240
Angle α, β, γ (deg.)90.000, 101.233, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y

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Components

#1: Protein 3C-like proteinase / SARS-CoV-2 3CL protease / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / ...SARS-CoV-2 3CL protease / 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 (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-SV6 / (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide / / TELAPREVIR, bound form / Telaprevir


Type: peptide-like, Peptide-like / Class: AntiviralAntiviral drug / Mass: 681.865 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H55N7O6 / Feature type: SUBJECT OF INVESTIGATION / References: TELAPREVIR, bound form / Comment: antivirus, protease inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.1 Å3/Da / Density % sol: 41.55 % / Description: plate-like
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7
Details: 22% PEG 4000, 100 mM HEPES pH 7.0, 3% DMSO, 1 mM telaprevir

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.48→53.83 Å / Num. obs: 46900 / % possible obs: 100 % / Redundancy: 10 % / CC1/2: 0.997 / Rmerge(I) obs: 0.135 / Rpim(I) all: 0.045 / Rrim(I) all: 0.142 / Net I/σ(I): 7.7
Reflection shellResolution: 1.48→1.51 Å / Redundancy: 7.2 % / Rmerge(I) obs: 3.003 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 2290 / CC1/2: 0.352 / Rrim(I) all: 3.229 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.18rc7_3834refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
AutoProcessdata reduction
Aimlessdata reduction
pointlessdata processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JYC
Resolution: 1.48→53.83 Å / SU ML: 0.2059 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.832
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2153 2000 4.27 %RANDOM
Rwork0.1847 44890 --
obs0.1861 46890 99.97 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.45 Å2
Refinement stepCycle: LAST / Resolution: 1.48→53.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2322 0 53 59 2434
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00792434
X-RAY DIFFRACTIONf_angle_d1.08633318
X-RAY DIFFRACTIONf_chiral_restr0.0828381
X-RAY DIFFRACTIONf_plane_restr0.0075427
X-RAY DIFFRACTIONf_dihedral_angle_d18.3712852
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.48-1.520.37891410.29253175X-RAY DIFFRACTION99.85
1.52-1.560.35251420.26823174X-RAY DIFFRACTION99.91
1.56-1.60.29151410.24213179X-RAY DIFFRACTION99.97
1.6-1.660.2841440.22543230X-RAY DIFFRACTION99.97
1.66-1.710.27461420.20653181X-RAY DIFFRACTION99.97
1.71-1.780.25571430.20193204X-RAY DIFFRACTION100
1.78-1.860.23741420.19693178X-RAY DIFFRACTION100
1.86-1.960.27251420.18313198X-RAY DIFFRACTION100
1.96-2.090.25081430.17863197X-RAY DIFFRACTION100
2.09-2.250.22161420.17893192X-RAY DIFFRACTION100
2.25-2.470.2311430.18433223X-RAY DIFFRACTION99.97
2.47-2.830.20411430.23220X-RAY DIFFRACTION100
2.83-3.570.22681440.19683236X-RAY DIFFRACTION100
3.57-53.830.1741480.16193303X-RAY DIFFRACTION99.88

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