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Entry
Database: PDB / ID: 9kgj
TitleDiscovery of an orally bioavailable reversible covalent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity
Components
  • (S)-3-((S)-3-cyclobutyl-2-((R)-2-cyclopentyl-N-methyl-2-pivalamidoacetamido)propanamido)-N-cyclopropyl-2-oxo-4-((S)-2-oxopiperidin-3-yl)butanamide
  • 3C-like proteinase nsp5
KeywordsHYDROLASE/INHIBOTOR / Protease / COV2 / HYDROLASE / HYDROLASE-INHIBOTOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 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 / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 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 / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / snRNP Assembly / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / SARS-CoV-2 modulates host translation machinery / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / regulation of autophagy / viral protein processing / lyase activity / 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 / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell nucleus / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
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 / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / Betacoronavirus single-stranded poly(A) binding domain / 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 / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-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 3Ecto domain 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
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.37 Å
AuthorsBaburajendran, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 M pro Inhibitor with Pan-Coronavirus Activity.
Authors: Tan, Q.W. / Vankadara, S. / Fong, J.Y. / See, Y.Y. / Baburajendran, N. / Ng, P.S. / Xu, W. / Yeo, Y.K. / Wang, W. / Low, C.H. / Tan, L.H. / Ju Tay, E.G. / Wong, Y.X. / Huang, C. / Sim, S. / ...Authors: Tan, Q.W. / Vankadara, S. / Fong, J.Y. / See, Y.Y. / Baburajendran, N. / Ng, P.S. / Xu, W. / Yeo, Y.K. / Wang, W. / Low, C.H. / Tan, L.H. / Ju Tay, E.G. / Wong, Y.X. / Huang, C. / Sim, S. / Ang, S.H. / Min Toh, H.H. / Mohammad, J. / Wang, G. / Liu, B. / Tan, S.T. / Kwek, P.Z. / Dawson, M.D. / Oh, Q.Y. / Koh, X. / Joy, J. / Lee, M.A. / Stunkel, W. / Pendharkar, V. / Hentze, H. / Lim, S.P. / Ethirajulu, K. / Brian Chia, C.S. / Cherian, J.
History
DepositionNov 8, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 20, 2025Provider: 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 nsp5
B: 3C-like proteinase nsp5
C: (S)-3-((S)-3-cyclobutyl-2-((R)-2-cyclopentyl-N-methyl-2-pivalamidoacetamido)propanamido)-N-cyclopropyl-2-oxo-4-((S)-2-oxopiperidin-3-yl)butanamide
D: (S)-3-((S)-3-cyclobutyl-2-((R)-2-cyclopentyl-N-methyl-2-pivalamidoacetamido)propanamido)-N-cyclopropyl-2-oxo-4-((S)-2-oxopiperidin-3-yl)butanamide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,7466
Polymers69,5434
Non-polymers2022
Water7,242402
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.969, 99.698, 59.828
Angle α, β, γ (deg.)90.000, 108.758, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 34237.000 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: Protein/peptide (S)-3-((S)-3-cyclobutyl-2-((R)-2-cyclopentyl-N-methyl-2-pivalamidoacetamido)propanamido)-N-cyclopropyl-2-oxo-4-((S)-2-oxopiperidin-3-yl)butanamide


Mass: 534.688 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-A1L7M / cyclopropylcarbamic acid


Mass: 101.104 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H7NO2 / Feature type: SUBJECT OF INVESTIGATION
#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: 2.26 Å3/Da / Density % sol: 45.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 4% v/v TacsimateTM pH 5.0, 12% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95365 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95365 Å / Relative weight: 1
ReflectionResolution: 1.37→46.96 Å / Num. obs: 128218 / % possible obs: 99.3 % / Redundancy: 6.8 % / Biso Wilson estimate: 15.04 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.2
Reflection shellResolution: 1.37→1.4 Å / Num. unique obs: 5987 / CC1/2: 0.677

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y2G

6y2g


Resolution: 1.37→46.96 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.2196
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2476 1976 1.55 %
Rwork0.2154 125110 -
obs0.2159 127086 98.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.92 Å2
Refinement stepCycle: LAST / Resolution: 1.37→46.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4606 0 86 402 5094
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01094801
X-RAY DIFFRACTIONf_angle_d1.24656537
X-RAY DIFFRACTIONf_chiral_restr0.1034743
X-RAY DIFFRACTIONf_plane_restr0.0105842
X-RAY DIFFRACTIONf_dihedral_angle_d25.7038684
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.37-1.410.63021150.56468224X-RAY DIFFRACTION90.5
1.41-1.450.34871620.33549020X-RAY DIFFRACTION99.73
1.45-1.490.39991330.33739036X-RAY DIFFRACTION99.73
1.49-1.540.351530.29329005X-RAY DIFFRACTION99.78
1.54-1.590.26891330.23159063X-RAY DIFFRACTION99.97
1.59-1.660.25911450.22269055X-RAY DIFFRACTION100
1.66-1.730.22281450.20859034X-RAY DIFFRACTION99.98
1.73-1.820.22841550.21439080X-RAY DIFFRACTION99.98
1.82-1.940.30031240.26588510X-RAY DIFFRACTION93.64
1.94-2.090.2561390.22448982X-RAY DIFFRACTION99.27
2.09-2.30.26451370.22888813X-RAY DIFFRACTION97.02
2.3-2.630.25521460.20999081X-RAY DIFFRACTION99.96
2.63-3.310.21931440.20669111X-RAY DIFFRACTION99.87
3.31-46.960.20021450.16379096X-RAY DIFFRACTION98.9

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