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- PDB-9pah: Crystal structure of SARS-CoV-2 3CLpro with ALG-097655 (Inhibitor 2) -

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Basic information

Entry
Database: PDB / ID: 9pah
TitleCrystal structure of SARS-CoV-2 3CLpro with ALG-097655 (Inhibitor 2)
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / CoV-2 3CLpro / Mpro / Nsp5 / ALG-097655 / INHIBITOR 2
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 / cysteine-type deubiquitinase activity / ubiquitinyl hydrolase 1 / 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 / DNA-templated transcription / lipid binding / 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: 1.65 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)69,0006
Polymers67,6512
Non-polymers1,3494
Water7,242402
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein exists as an dimer in solution
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3050 Å2
ΔGint-27 kcal/mol
Surface area25210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.141, 60.921, 63.795
Angle α, β, γ (deg.)78.623, 68.407, 70.496
Int Tables number1
Space group name H-MP1
Space group name HallP1

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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: 33825.547 Da / Num. of mol.: 2
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 (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#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 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / 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: 2.82 Å3/Da / Density % sol: 56.33 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting 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: Oct 9, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.902 Å / Relative weight: 1
ReflectionResolution: 1.44→33.2 Å / Num. obs: 86527 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.05 / Rrim(I) all: 0.132 / Χ2: 0.9 / Net I/σ(I): 8.5
Reflection shellResolution: 1.44→1.52 Å / Redundancy: 6.3 % / Rmerge(I) obs: 1.693 / Num. unique obs: 9861 / CC1/2: 0.419 / Rpim(I) all: 0.731 / Rrim(I) all: 1 / Χ2: 0.83

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: SAD / Resolution: 1.65→10 Å / SU ML: 0.2336 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 26.316
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2439 4390 5.07 %
Rwork0.2163 82137 -
obs0.2178 86527 97.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.71 Å2
Refinement stepCycle: LAST / Resolution: 1.65→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4658 0 90 402 5150
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00684914
X-RAY DIFFRACTIONf_angle_d0.91816711
X-RAY DIFFRACTIONf_chiral_restr0.0518755
X-RAY DIFFRACTIONf_plane_restr0.007867
X-RAY DIFFRACTIONf_dihedral_angle_d15.19431769
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.670.34891350.32722664X-RAY DIFFRACTION95.92
1.67-1.690.33091430.31242694X-RAY DIFFRACTION95.84
1.69-1.710.36271540.30432659X-RAY DIFFRACTION96.04
1.71-1.730.33751380.29632743X-RAY DIFFRACTION96.23
1.73-1.750.31011400.28922659X-RAY DIFFRACTION96.02
1.75-1.780.29941280.29072739X-RAY DIFFRACTION96.66
1.78-1.80.32341430.28092733X-RAY DIFFRACTION96.48
1.8-1.830.33881430.2782750X-RAY DIFFRACTION96.85
1.83-1.860.30861690.2692637X-RAY DIFFRACTION96.63
1.86-1.890.25441440.25342759X-RAY DIFFRACTION97.03
1.89-1.920.28281520.24312703X-RAY DIFFRACTION96.91
1.92-1.960.24811610.23812681X-RAY DIFFRACTION96.93
1.96-1.990.24571460.22662777X-RAY DIFFRACTION97.21
1.99-2.040.26121180.21472736X-RAY DIFFRACTION97.27
2.04-2.080.2431350.21242734X-RAY DIFFRACTION97.29
2.08-2.130.24421610.21322754X-RAY DIFFRACTION97.65
2.13-2.180.26011390.20622776X-RAY DIFFRACTION97.82
2.18-2.240.24011340.20342734X-RAY DIFFRACTION97.39
2.24-2.310.24971530.20942716X-RAY DIFFRACTION97.98
2.31-2.380.23271400.20462747X-RAY DIFFRACTION98.06
2.38-2.470.25181270.20982801X-RAY DIFFRACTION98.02
2.47-2.560.24811430.21372771X-RAY DIFFRACTION98.31
2.56-2.680.28271830.21782732X-RAY DIFFRACTION98.41
2.68-2.820.261450.22192785X-RAY DIFFRACTION98.45
2.82-30.27871480.21722735X-RAY DIFFRACTION98.67
3-3.230.21451540.2162799X-RAY DIFFRACTION98.86
3.23-3.550.22521570.20232779X-RAY DIFFRACTION99.06
3.55-4.070.17611380.1752764X-RAY DIFFRACTION99.15
4.07-5.120.2041520.17522802X-RAY DIFFRACTION99.29
5.12-100.23121670.19782774X-RAY DIFFRACTION99.49
Refinement TLS params.Method: refined / Origin x: 0.0128347506711 Å / Origin y: -0.116745080151 Å / Origin z: 0.842729476545 Å
111213212223313233
T0.140459563297 Å2-0.00957052836964 Å2-0.0115400555754 Å2-0.107431846524 Å2-0.0104405326989 Å2--0.10926098662 Å2
L1.38268850127 °2-0.224600860029 °2-0.294339989898 °2-0.493514276791 °20.0123321807637 °2--0.652749621783 °2
S0.0155588327706 Å °0.0130225379155 Å °-0.0196643561513 Å °-0.0124024318448 Å °-0.0102321062883 Å °0.0585954343211 Å °0.00779155937707 Å °0.0920084451221 Å °-0.01115561699 Å °
Refinement TLS groupSelection details: all

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