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- PDB-9atj: Crystal structure of MERS 3CL protease in complex with a m-chloro... -

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Basic information

Entry
Database: PDB / ID: 9atj
TitleCrystal structure of MERS 3CL protease in complex with a m-chlorobenzyl 2-pyrrolidone inhibitor
Components3C-like proteinase nsp5
KeywordsHYDROLASE/INHIBITOR / MERS / 3CL protease inhibitors / COVID-19 / viral protein / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / SARS coronavirus main proteinase / endonuclease activity / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity ...host cell membrane / viral genome replication / methyltransferase activity / SARS coronavirus main proteinase / endonuclease activity / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / omega peptidase activity / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / viral protein processing / host cell perinuclear region of cytoplasm / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / proteolysis / zinc ion binding / membrane
Similarity search - Function
Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, 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 / NSP1, C-terminal domain, betacoronavirus / : ...Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, 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 / NSP1, C-terminal domain, betacoronavirus / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / : / : / Coronavirus replicase NSP7 / Coronavirus 3Ecto 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. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, 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 / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
: / : / Replicase polyprotein 1a
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsLiu, L. / Lovell, S. / Battaile, K.P. / Dampalla, C.S. / Groutas, W.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI130092 United States
National Institutes of Health/Office of the DirectorS10OD030394 United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies.
Authors: Dampalla, C.S. / Kim, Y. / Zabiegala, A. / Howard, D.J. / Nguyen, H.N. / Madden, T.K. / Thurman, H.A. / Cooper, A. / Liu, L. / Battaile, K.P. / Lovell, S. / Chang, K.O. / Groutas, W.C.
History
DepositionFeb 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5734
Polymers34,3141
Non-polymers1,2593
Water4,324240
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1468
Polymers68,6282
Non-polymers2,5176
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2750 Å2
ΔGint-32 kcal/mol
Surface area24270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.219, 58.010, 49.855
Angle α, β, γ (deg.)90.00, 112.47, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-621-

HOH

21A-727-

HOH

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Components

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


Mass: 34314.242 Da / Num. of mol.: 1 / Fragment: UNP residues 3248-3553
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Gene: 1a / Plasmid: pET-28 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: K9N638, SARS coronavirus main proteinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Mg
#3: Chemical ChemComp-A1AGJ / (1S,2S)-2-({N-[({(2S)-1-[(3-chlorophenyl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 617.111 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H37ClN4O9S
#4: Chemical ChemComp-A1AGI / (1R,2S)-2-({N-[({(2S)-1-[(3-chlorophenyl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 617.111 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C26H37ClN4O9S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.97 Å3/Da / Density % sol: 37.59 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 15% v/v PEG400, 100 mM MES, pH 6.0, 100 mM calcium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Oct 5, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.4→49.3 Å / Num. obs: 49448 / % possible obs: 94.3 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.021 / Rrim(I) all: 0.055 / Χ2: 1.02 / Net I/σ(I): 15.2 / Num. measured all: 327562
Reflection shellResolution: 1.4→1.44 Å / % possible obs: 67.3 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.825 / Num. measured all: 15939 / Num. unique obs: 2591 / CC1/2: 0.701 / Rpim(I) all: 0.353 / Rrim(I) all: 0.9 / Χ2: 1.11 / Net I/σ(I) obs: 2.1

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.4→23.82 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 16.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1696 2396 4.85 %
Rwork0.137 --
obs0.1386 49421 94.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.4→23.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2298 0 75 240 2613
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012551
X-RAY DIFFRACTIONf_angle_d1.1133505
X-RAY DIFFRACTIONf_dihedral_angle_d14.421927
X-RAY DIFFRACTIONf_chiral_restr0.087402
X-RAY DIFFRACTIONf_plane_restr0.009448
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.430.2926990.23781881X-RAY DIFFRACTION65
1.43-1.460.24761350.19892477X-RAY DIFFRACTION84
1.46-1.490.23431270.16532730X-RAY DIFFRACTION93
1.49-1.530.21091370.13752766X-RAY DIFFRACTION95
1.53-1.570.19791500.12362803X-RAY DIFFRACTION95
1.57-1.620.14011520.11422763X-RAY DIFFRACTION96
1.62-1.670.15171360.11812834X-RAY DIFFRACTION96
1.67-1.730.16091410.11532797X-RAY DIFFRACTION96
1.73-1.80.16541460.12172846X-RAY DIFFRACTION97
1.8-1.880.16891480.12252833X-RAY DIFFRACTION97
1.88-1.980.17091420.11312834X-RAY DIFFRACTION97
1.98-2.10.15061460.11362885X-RAY DIFFRACTION97
2.1-2.270.15221410.12432889X-RAY DIFFRACTION98
2.27-2.50.15541380.12642875X-RAY DIFFRACTION98
2.5-2.860.15171460.13962906X-RAY DIFFRACTION98
2.86-3.60.16751630.14712908X-RAY DIFFRACTION98
3.6-23.820.18161490.14962998X-RAY DIFFRACTION99

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