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- PDB-9pa9: Crystal structure of SARS-CoV-2 3CLpro with ALG-097608 (Inhibitor 1) -

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Basic information

Entry
Database: PDB / ID: 9pa9
TitleCrystal structure of SARS-CoV-2 3CLpro with ALG-097608 (Inhibitor 1)
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / CoV-2 / 3CLpro / Mpro / Nsp5 ALG-097608 / INHIBITOR 1 / pan coronavirus drug
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / host cell endosome / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / mRNA guanylyltransferase / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / DNA helicase / symbiont-mediated suppression of host NF-kappaB cascade / SARS-CoV-2 modulates host translation machinery / symbiont-mediated perturbation of host ubiquitin-like protein modification / host cell Golgi apparatus / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / lipid binding / DNA-templated transcription / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / 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 / : ...RNA-dependent RNA polymerase, SARS-CoV-like / 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 / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / Betacoronavirus single-stranded poly(A) binding domain / 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / Coronavirus replicase NSP2, N-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 Nsp3 ectodomain (3Ecto) profile.
Similarity search - Domain/homology
: / PHOSPHATE ION / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 1.83 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,1395
Polymers33,2931
Non-polymers8464
Water3,801211
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,27910
Polymers66,5862
Non-polymers1,6938
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3330 Å2
ΔGint-33 kcal/mol
Surface area25360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.636, 80.619, 54.496
Angle α, β, γ (deg.)90.00, 116.81, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-402-

PO4

21A-402-

PO4

31A-403-

PO4

41A-403-

PO4

51A-502-

HOH

61A-641-

HOH

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Components

#1: Protein 3C-like proteinase nsp5 / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33292.965 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
#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.: 1 / Source method: obtained synthetically / Formula: C25H32F5N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.87 Å3/Da / Density % sol: 57.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 mM Sodium Phosphate monobasic and 0.1 M MES pH 6.0 and 20% PEG 4000

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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: 0.902 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: 0.902 Å / Relative weight: 1
ReflectionResolution: 1.83→31.04 Å / Num. obs: 33330 / % possible obs: 100 % / Redundancy: 7 % / CC1/2: 0.995 / Rmerge(I) obs: 0.182 / Rpim(I) all: 0.074 / Rrim(I) all: 0.197 / Χ2: 0.91 / Net I/σ(I): 6.6 / Num. measured all: 234202
Reflection shellResolution: 1.83→1.93 Å / Redundancy: 7.1 % / Rmerge(I) obs: 1.004 / Num. unique obs: 4834 / CC1/2: 0.395 / Rpim(I) all: 0.405 / Rrim(I) all: 0.9 / Χ2: 0.77

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: SAD / Resolution: 1.83→31.04 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2211 1630 4.89 %
Rwork0.1791 --
obs0.1811 33325 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.83→31.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2329 0 54 211 2594
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072468
X-RAY DIFFRACTIONf_angle_d1.0633373
X-RAY DIFFRACTIONf_dihedral_angle_d16.271881
X-RAY DIFFRACTIONf_chiral_restr0.067379
X-RAY DIFFRACTIONf_plane_restr0.008437
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.83-1.880.2811470.28872614X-RAY DIFFRACTION100
1.88-1.940.31471300.26042635X-RAY DIFFRACTION100
1.94-2.010.2831400.24672602X-RAY DIFFRACTION100
2.01-2.090.27511390.22182638X-RAY DIFFRACTION100
2.09-2.190.2321320.20292653X-RAY DIFFRACTION100
2.19-2.30.21811390.18952611X-RAY DIFFRACTION100
2.3-2.450.25231300.18832652X-RAY DIFFRACTION100
2.45-2.640.20211300.17882641X-RAY DIFFRACTION100
2.64-2.90.23291410.18222633X-RAY DIFFRACTION100
2.9-3.320.2121340.17972645X-RAY DIFFRACTION100
3.32-4.180.19371390.14572666X-RAY DIFFRACTION100
4.18-31.040.17211290.13352705X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -5.648 Å / Origin y: -0.4744 Å / Origin z: 12.1835 Å
111213212223313233
T0.1044 Å2-0.0196 Å20.0011 Å2-0.1326 Å2-0.0156 Å2--0.1337 Å2
L0.7452 °20.181 °2-0.205 °2-1.1412 °20.3994 °2--1.5311 °2
S0.0035 Å °-0.0201 Å °-0.0293 Å °0.0294 Å °0.0367 Å °-0.1175 Å °0.0259 Å °-0.0752 Å °-0.0265 Å °
Refinement TLS groupSelection details: all

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