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- PDB-9paa: Crystal structure of HCoV-229E 3CLpro with ALG-0987608 (inhibitor 1) -

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Basic information

Entry
Database: PDB / ID: 9paa
TitleCrystal structure of HCoV-229E 3CLpro with ALG-0987608 (inhibitor 1)
Components3C-like proteinase
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / HCoV 229E / 3CLprotease / Mpro / Nsp5 / ALG-097608 / pan coronovirus durg
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 / MOLECULAR REPLACEMENT / Resolution: 1.41 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,5815
Polymers65,9112
Non-polymers1,6703
Water9,872548
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein exist as a homodimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4000 Å2
ΔGint-7 kcal/mol
Surface area24780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.287, 76.374, 77.013
Angle α, β, γ (deg.)90.00, 91.60, 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: 32955.449 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 (E. coli)
References: UniProt: P0C6X1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#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.: 2 / Source method: obtained synthetically / Formula: C25H32F5N5O4 / Feature type: SUBJECT OF INVESTIGATION
#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.: 548 / 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: 48.25 %
Crystal growTemperature: 277.15 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: 0.92019 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: 1.41→34.37 Å / Num. obs: 118296 / % possible obs: 99.8 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.127 / Rpim(I) all: 0.052 / Rrim(I) all: 0.138 / Χ2: 0.82 / Net I/σ(I): 7.9 / Num. measured all: 811356
Reflection shellResolution: 1.41→1.49 Å / % possible obs: 98.8 % / Redundancy: 5.8 % / Rmerge(I) obs: 1.26 / Num. measured all: 98431 / Num. unique obs: 17026 / CC1/2: 0.447 / Rpim(I) all: 0.569 / Rrim(I) all: 1.385 / Χ2: 0.69 / Net I/σ(I) obs: 1.3

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→34.37 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2169 5827 4.93 %
Rwork0.1931 --
obs0.1942 118225 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.41→34.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4618 0 115 548 5281
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064851
X-RAY DIFFRACTIONf_angle_d0.9676574
X-RAY DIFFRACTIONf_dihedral_angle_d15.9741701
X-RAY DIFFRACTIONf_chiral_restr0.093714
X-RAY DIFFRACTIONf_plane_restr0.006837
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.41-1.430.31931820.3023624X-RAY DIFFRACTION97
1.43-1.440.30461970.2963659X-RAY DIFFRACTION98
1.44-1.460.30032050.27523694X-RAY DIFFRACTION99
1.46-1.480.26991660.26153765X-RAY DIFFRACTION99
1.48-1.50.28061620.26033730X-RAY DIFFRACTION100
1.5-1.520.28881640.23793791X-RAY DIFFRACTION100
1.52-1.540.27671750.22623771X-RAY DIFFRACTION100
1.54-1.560.24061620.2343757X-RAY DIFFRACTION100
1.56-1.590.24921910.2183717X-RAY DIFFRACTION100
1.59-1.610.25331930.22953764X-RAY DIFFRACTION100
1.61-1.640.27111840.22543755X-RAY DIFFRACTION100
1.64-1.670.25931620.22043777X-RAY DIFFRACTION100
1.67-1.70.20722010.2043738X-RAY DIFFRACTION100
1.7-1.740.25371850.20673765X-RAY DIFFRACTION100
1.74-1.780.22341840.20513778X-RAY DIFFRACTION100
1.78-1.820.20682190.19263701X-RAY DIFFRACTION100
1.82-1.860.23562300.19043698X-RAY DIFFRACTION100
1.86-1.910.22621840.18633766X-RAY DIFFRACTION100
1.91-1.970.19862270.19333754X-RAY DIFFRACTION100
1.97-2.030.2051850.18923714X-RAY DIFFRACTION100
2.03-2.110.2272670.18223690X-RAY DIFFRACTION100
2.11-2.190.20742200.18173725X-RAY DIFFRACTION100
2.19-2.290.21261900.18653762X-RAY DIFFRACTION100
2.29-2.410.21221530.18883824X-RAY DIFFRACTION100
2.41-2.560.2092320.19423737X-RAY DIFFRACTION100
2.56-2.760.22872070.19343729X-RAY DIFFRACTION100
2.76-3.040.21861850.19373787X-RAY DIFFRACTION100
3.04-3.480.2132310.18953752X-RAY DIFFRACTION100
3.48-4.380.18321630.16413829X-RAY DIFFRACTION100
4.38-100.17162210.15373845X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 5.8993 Å / Origin y: -0.4145 Å / Origin z: 22.6588 Å
111213212223313233
T0.1189 Å20.0015 Å20.0107 Å2-0.1183 Å2-0.0033 Å2--0.1114 Å2
L0.284 °20.1362 °20.0638 °2-0.3467 °20.0068 °2--0.2863 °2
S-0.0217 Å °0.0578 Å °-0.0182 Å °-0.0437 Å °0.0331 Å °-0.0272 Å °-0.0283 Å °0.0051 Å °-0.0113 Å °
Refinement TLS groupSelection details: all

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