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- PDB-9paj: Crystal structure of HCoV-229E 3CLpro with ALG-0987655 (inhibitor 2) -

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Basic information

Entry
Database: PDB / ID: 9paj
TitleCrystal structure of HCoV-229E 3CLpro with ALG-0987655 (inhibitor 2)
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / HCoV 229E / Nsp5 / ALG-097655 / PAN CORONOVIRUS DRUG / INHIBITOR 2
Function / homology
Function and homology information


host cell membrane / Lyases; Phosphorus-oxygen lyases / endonuclease activity / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / mRNA guanylyltransferase / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity ...host cell membrane / Lyases; Phosphorus-oxygen lyases / endonuclease activity / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / mRNA guanylyltransferase / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / methyltransferase cap1 / DNA helicase / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase activity / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / lyase activity / viral protein processing / host cell perinuclear region of cytoplasm / RNA helicase / 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 / DNA-templated transcription / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Coronavirus replicase NSP2, C-terminal / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus ...Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Coronavirus replicase NSP2, C-terminal / 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. / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / 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. / 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
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesHuman coronavirus 229E
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 1.32 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 1.0May 6, 2026Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8735
Polymers66,1672
Non-polymers1,7063
Water10,323573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein exists as dimer in solution
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3980 Å2
ΔGint-12 kcal/mol
Surface area25170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.311, 76.453, 76.840
Angle α, β, γ (deg.)90.00, 91.44, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp / M-PRO / nsp5 / p34


Mass: 33083.578 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human coronavirus 229E / Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0C6X1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-A1CHJ / (1R,2S,3S,6R,7S)-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-[(2S)-4,4,4-trifluoro-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0~2,6~]dec-8-ene-3-carboxamide (non-preferred name)


Mass: 579.535 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H31F6N5O4
#3: Chemical ChemComp-12P / DODECAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 546.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H50O13 / Feature type: SUBJECT OF INVESTIGATION / Comment: precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 573 / 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: 2.38 Å3/Da / Density % sol: 48.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1 M Tris pH 8.0 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: 0.902 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 8, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.902 Å / Relative weight: 1
ReflectionResolution: 1.2→34.22 Å / Num. obs: 143908 / % possible obs: 100 % / Redundancy: 7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.133 / Rpim(I) all: 0.054 / Rrim(I) all: 0.144 / Χ2: 0.89 / Net I/σ(I): 8.4
Reflection shellResolution: 1.32→1.39 Å / Redundancy: 7.1 % / Rmerge(I) obs: 1.716 / Num. unique obs: 20926 / CC1/2: 0.383 / Rpim(I) all: 0.694 / Rrim(I) all: 0.9 / Χ2: 0.77

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: SAD / Resolution: 1.32→34.22 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1906 6816 4.74 %
Rwork0.154 --
obs0.1558 143704 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.32→34.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4635 0 117 573 5325
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054884
X-RAY DIFFRACTIONf_angle_d0.8126620
X-RAY DIFFRACTIONf_dihedral_angle_d16.2491733
X-RAY DIFFRACTIONf_chiral_restr0.074718
X-RAY DIFFRACTIONf_plane_restr0.006844
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.32-1.340.29332260.27814482X-RAY DIFFRACTION99
1.34-1.350.32392350.26774509X-RAY DIFFRACTION99
1.35-1.370.27832070.25914571X-RAY DIFFRACTION99
1.37-1.390.29232060.25274482X-RAY DIFFRACTION100
1.39-1.40.29752070.24944592X-RAY DIFFRACTION100
1.4-1.420.30192040.24414545X-RAY DIFFRACTION100
1.42-1.440.28372100.23244625X-RAY DIFFRACTION100
1.44-1.470.23912070.21484527X-RAY DIFFRACTION100
1.47-1.490.23912410.20194553X-RAY DIFFRACTION100
1.49-1.510.2582430.19344514X-RAY DIFFRACTION100
1.51-1.540.22182120.18434575X-RAY DIFFRACTION100
1.54-1.570.23212290.17654587X-RAY DIFFRACTION100
1.57-1.60.21692130.16744570X-RAY DIFFRACTION100
1.6-1.630.21182650.15974487X-RAY DIFFRACTION100
1.63-1.660.21852120.15694625X-RAY DIFFRACTION100
1.66-1.70.20612210.14964530X-RAY DIFFRACTION100
1.7-1.750.19412120.15064592X-RAY DIFFRACTION100
1.75-1.790.20612050.15024579X-RAY DIFFRACTION100
1.79-1.850.18312370.13494556X-RAY DIFFRACTION100
1.85-1.910.18882250.1284594X-RAY DIFFRACTION100
1.91-1.970.15692430.13024533X-RAY DIFFRACTION100
1.97-2.050.19042400.12994552X-RAY DIFFRACTION100
2.05-2.150.16692550.13194530X-RAY DIFFRACTION100
2.15-2.260.1781880.13354631X-RAY DIFFRACTION100
2.26-2.40.1682760.13894519X-RAY DIFFRACTION100
2.4-2.590.19472250.14284594X-RAY DIFFRACTION100
2.59-2.850.17722200.14844599X-RAY DIFFRACTION100
2.85-3.260.16152540.14754559X-RAY DIFFRACTION100
3.26-4.10.16752410.13934616X-RAY DIFFRACTION100
4.1-100.16662570.1344660X-RAY DIFFRACTION100

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