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- PDB-9zj4: Crystal structure of SARS-CoV-2 3CL protease in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 9zj4
TitleCrystal structure of SARS-CoV-2 3CL protease in complex with inhibitor IKR-I-45
Components3C-like proteinase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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 / DNA helicase / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / 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 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / cysteine-type deubiquitinase 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 / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / DNA-templated transcription / 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 Nsp3 ectodomain (3Ecto) profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile.
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsUng, A.R. / Lovell, S. / Battaile, K.P. / Ilesinghe, I.K.R.S. / Groutas, W.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI161085 United States
National Institutes of Health/Office of the DirectorS10OD030394 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2026
Title: Structure-guided design of broad-spectrum inhibitors of coronaviral proteases embodying a 1,3,2-oxazaphospholidin-3-one scaffold as a versatile design element.
Authors: Nguyen, H.N. / Ranasinghe, P.S. / Ilesinghe, I.K.R.S. / Dampalla, C.S. / Rathnayake, A.D. / Liska, Z. / Jesri, A.M. / Azmi, Z. / Nevonen, D.E. / Kim, Y. / Ung, A.R. / Taylor, K.E. / Cooper, ...Authors: Nguyen, H.N. / Ranasinghe, P.S. / Ilesinghe, I.K.R.S. / Dampalla, C.S. / Rathnayake, A.D. / Liska, Z. / Jesri, A.M. / Azmi, Z. / Nevonen, D.E. / Kim, Y. / Ung, A.R. / Taylor, K.E. / Cooper, A. / Liu, L. / Battaile, K.P. / Thurman, H.A. / Gusachenko, E. / Lovell, S. / Groutas, W.C. / Chang, K.O.
History
DepositionDec 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5833
Polymers34,0691
Non-polymers5142
Water23413
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1666
Polymers68,1382
Non-polymers1,0284
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3140 Å2
ΔGint-32 kcal/mol
Surface area24760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.258, 54.912, 46.795
Angle α, β, γ (deg.)90.00, 101.89, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-401-

CL

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Components

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


Mass: 34068.805 Da / Num. of mol.: 1 / Fragment: Full Length
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Plasmid: pET-28 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-A1C2T / N~2~-[(2S,4S)-3-benzyl-4-methyl-2-oxo-1,3,2lambda~5~-oxazaphospholidin-2-yl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide


Mass: 478.522 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H35N4O5P / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.05 Å3/Da / Density % sol: 40.08 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 20% (w/v) PEG 6000, 100 mM MES pH 6.0, 200 mM sodium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.97856 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Nov 1, 2025
RadiationMonochromator: Double Crystal Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.44→49.03 Å / Num. obs: 10405 / % possible obs: 99.9 % / Redundancy: 6.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.112 / Rpim(I) all: 0.046 / Rrim(I) all: 0.121 / Χ2: 1.03 / Net I/σ(I): 12.1 / Num. measured all: 70801
Reflection shellResolution: 2.44→2.54 Å / % possible obs: 99.9 % / Redundancy: 6.8 % / Rmerge(I) obs: 1.326 / Num. measured all: 7933 / Num. unique obs: 1162 / CC1/2: 0.651 / Rpim(I) all: 0.547 / Rrim(I) all: 1.436 / Χ2: 1.07 / Net I/σ(I) obs: 1.7

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Processing

Software
NameVersionClassification
PHENIX(2.0_5875: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.44→49.03 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2656 496 4.77 %
Rwork0.2106 --
obs0.2132 10398 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.44→49.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2304 0 34 13 2351
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022391
X-RAY DIFFRACTIONf_angle_d0.5313260
X-RAY DIFFRACTIONf_dihedral_angle_d13.633851
X-RAY DIFFRACTIONf_chiral_restr0.041371
X-RAY DIFFRACTIONf_plane_restr0.004425
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.44-2.690.32031170.3012462X-RAY DIFFRACTION100
2.69-3.070.33281230.27842470X-RAY DIFFRACTION100
3.07-3.870.29261450.22072444X-RAY DIFFRACTION100
3.87-49.030.21591110.17332526X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.7063-1.37242.99283.3377-1.31372.30870.5787-0.4197-0.6150.09080.1972-0.13230.9248-0.0972-0.520.54430.0212-0.11890.303-0.01190.47558.4779-12.386213.4464
26.6022-1.13683.22644.48051.46134.78780.58-1.4933-1.02480.95380.13370.03730.8979-0.6145-0.66320.7727-0.0553-0.12670.67020.16180.624711.2892-21.847424.7601
32.7881-1.64543.1153.2237-1.27424.05210.51030.2701-0.4256-0.4152-0.049-0.11370.86630.5893-0.28890.53080.0735-0.05370.4274-0.0370.415711.0737-11.06538.8887
40.3619-0.42571.05364.0799-3.39754.35480.00190.09810.01730.3438-0.2839-0.5056-0.21790.83660.21310.30280.03190.03760.5097-0.05470.412214.16150.74888.3244
52.6823-0.1448-0.22466.46771.74264.78630.11480.12740.0563-0.53780.1255-0.7823-0.22370.2522-0.1560.398-0.0350.19970.507-0.0180.47513.56713.3412-9.4917
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 53 )
2X-RAY DIFFRACTION2chain 'A' and (resid 54 through 76 )
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 155 )
4X-RAY DIFFRACTION4chain 'A' and (resid 156 through 213 )
5X-RAY DIFFRACTION5chain 'A' and (resid 214 through 302 )

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