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- PDB-9pae: Crystal structure of HCoV OC43 3CLpro with ALG-097608 (inhibitor 1) -

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Basic information

Entry
Database: PDB / ID: 9pae
TitleCrystal structure of HCoV OC43 3CLpro with ALG-097608 (inhibitor 1)
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/inhibitor / 3CL Protease / Nsp5 / Pan coronavirus / ALG-097608 / INHIBITOR 1
Function / homology
Function and homology information


host cell membrane / endonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / symbiont-mediated suppression of host ISG15-protein conjugation / mRNA guanylyltransferase activity / omega peptidase activity / symbiont-mediated suppression of host NF-kappaB cascade ...host cell membrane / endonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / symbiont-mediated suppression of host ISG15-protein conjugation / mRNA guanylyltransferase activity / omega peptidase activity / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase activity / RNA helicase activity / lyase activity / single-stranded RNA binding / 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 / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / proteolysis / zinc ion binding / ATP binding
Similarity search - Function
RNA-dependent RNA polymerase, coronavirus HKU1-like / Coronavirus Nsp3 DPUP domain / Peptidase C30/C16, Betacoronavirus / Betacoronavirus, lineage A, NSP1 / NSP3, DPUP domain, murine hepatitis virus-like / Non-structural protein 2, MHV-like / Peptidase C16 family / Betacoronavirus, lineage A, NSP1 / AAA domain / Nonstructural protein 14, betacoronavirus ...RNA-dependent RNA polymerase, coronavirus HKU1-like / Coronavirus Nsp3 DPUP domain / Peptidase C30/C16, Betacoronavirus / Betacoronavirus, lineage A, NSP1 / NSP3, DPUP domain, murine hepatitis virus-like / Non-structural protein 2, MHV-like / Peptidase C16 family / Betacoronavirus, lineage A, NSP1 / AAA domain / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / 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 / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) 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 / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / 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. / 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 (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 Nsp3 ectodomain (3Ecto) 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
Similarity search - Domain/homology
: / ORF1ab polyprotein
Similarity search - Component
Biological speciesHuman coronavirus OC43
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 Å
AuthorsReddem, E.R. / Forouhad, F. / Shapiro, L. / Stoycheva, A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)MAVDA-1U19AI1711401 United States
Bill & Melinda Gates FoundationINV-016167 United States
CitationJournal: Structure / Year: 2026
Title: Structural basis for pan-coronavirus inhibition of 3CL protease.
Authors: Reddem, E.R. / Forouhar, F. / Liu, C. / Stevens, S.K. / Jekle, A. / Chang, C.W. / Oswal, N. / McGowan, D.C. / Vandyck, K. / Smith, D.B. / Raboisson, P. / Beigelman, L.N. / Katsamba, P.S. / ...Authors: Reddem, E.R. / Forouhar, F. / Liu, C. / Stevens, S.K. / Jekle, A. / Chang, C.W. / Oswal, N. / McGowan, D.C. / Vandyck, K. / Smith, D.B. / Raboisson, P. / Beigelman, L.N. / Katsamba, P.S. / Bahna, F. / Mannepalli, S. / Blatt, L. / Perlin, D. / Symons, J.A. / Shapiro, L. / Stoycheva, A.D.
History
DepositionJun 25, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2026Provider: repository / Type: Initial release
Revision 1.1Feb 18, 2026Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 15, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,2608
Polymers134,0144
Non-polymers2,2464
Water7,440413
1
A: 3C-like proteinase
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,1304
Polymers67,0072
Non-polymers1,1232
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3060 Å2
ΔGint-16 kcal/mol
Surface area25210 Å2
MethodPISA
2
C: 3C-like proteinase
D: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,1304
Polymers67,0072
Non-polymers1,1232
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3000 Å2
ΔGint-18 kcal/mol
Surface area25290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.087, 106.499, 107.309
Angle α, β, γ (deg.)90.00, 127.55, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-608-

HOH

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Components

#1: Protein
3C-like proteinase


Mass: 33503.402 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human coronavirus OC43 / Gene: Pp1ab / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: U3M6R3
#2: Chemical
ChemComp-A1CHF / (1R,2R,3S,6S,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-10,10-difluoro-N-{(1E,2R)-1-imino-3-[(3R)-2-oxo-3,4-dihydro-2H-pyrrol-3-yl]propan-2-yl}-4-azatricyclo[5.2.1.0~2,6~]decane-3-carboxamide (non-preferred name)


Mass: 561.545 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H32F5N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 413 / 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: 2.77 Å3/Da / Density % sol: 59.19 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2M Potassium thiocyanate, 0.1 M Bis-Tris pH 8.5 and 20% PEG3350

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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: 0.92019 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 24, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92019 Å / Relative weight: 1
ReflectionResolution: 1.87→33.96 Å / Num. obs: 63060 / % possible obs: 100 % / Redundancy: 13.9 % / CC1/2: 0.99 / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.124 / Rrim(I) all: 0.42 / Χ2: 1 / Net I/σ(I): 5.9
Reflection shellResolution: 1.87→1.97 Å / Redundancy: 14 % / Rmerge(I) obs: 1.7 / Num. unique obs: 8297 / CC1/2: 0.408 / Rpim(I) all: 0.837 / Rrim(I) all: 0.9 / Χ2: 0.96

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.31→33.96 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2803 3069 4.87 %
Rwork0.214 --
obs0.2172 63060 98.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.31→33.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9372 0 156 413 9941
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0079750
X-RAY DIFFRACTIONf_angle_d1.07313282
X-RAY DIFFRACTIONf_dihedral_angle_d14.6593450
X-RAY DIFFRACTIONf_chiral_restr0.061530
X-RAY DIFFRACTIONf_plane_restr0.0061664
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.31-2.350.40521500.34962646X-RAY DIFFRACTION97
2.35-2.390.39081470.32612689X-RAY DIFFRACTION97
2.39-2.430.35131330.30112708X-RAY DIFFRACTION98
2.43-2.470.33851610.29712650X-RAY DIFFRACTION98
2.47-2.520.34291560.28862704X-RAY DIFFRACTION98
2.52-2.570.34621530.27442678X-RAY DIFFRACTION98
2.57-2.630.33651260.27652724X-RAY DIFFRACTION98
2.63-2.690.35991240.26912726X-RAY DIFFRACTION98
2.69-2.750.35331360.25842719X-RAY DIFFRACTION98
2.75-2.830.29791600.25092692X-RAY DIFFRACTION98
2.83-2.910.33331650.24592681X-RAY DIFFRACTION99
2.91-3.010.26821480.23482710X-RAY DIFFRACTION99
3.01-3.110.32141610.22962700X-RAY DIFFRACTION99
3.11-3.240.27731350.2232749X-RAY DIFFRACTION99
3.24-3.390.31521090.22252773X-RAY DIFFRACTION99
3.39-3.560.28971200.21742753X-RAY DIFFRACTION99
3.56-3.790.29591000.19952792X-RAY DIFFRACTION99
3.79-4.080.24091560.1852730X-RAY DIFFRACTION99
4.08-4.490.22141610.15842740X-RAY DIFFRACTION99
4.49-5.140.20241130.15282793X-RAY DIFFRACTION99
5.14-6.460.21741210.17142792X-RAY DIFFRACTION99
6.46-100.2151340.16042842X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 30.0352 Å / Origin y: -4.1142 Å / Origin z: 25.1629 Å
111213212223313233
T0.0781 Å2-0.0124 Å2-0.0224 Å2-0.1004 Å20.002 Å2--0.0921 Å2
L0.1567 °20.1931 °2-0.2442 °2-0.3277 °2-0.2104 °2--0.3101 °2
S0.0405 Å °-0.0095 Å °0.0247 Å °0.0517 Å °-0.0281 Å °0.0286 Å °-0.0295 Å °-0.0031 Å °0.0003 Å °
Refinement TLS groupSelection details: all

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