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- PDB-8aj0: Mpro of SARS COV-2 in complex with the RK-90 inhibitor -

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Basic information

Entry
Database: PDB / ID: 8aj0
TitleMpro of SARS COV-2 in complex with the RK-90 inhibitor
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / inhibitor complex / SARS-COV-2
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 / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...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 / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / 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 / host cell endoplasmic reticulum-Golgi intermediate compartment / double membrane vesicle viral factory outer membrane / 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 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / 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 / 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 / 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
Chem-MJ0 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.519 Å
AuthorsEl Kilani, H. / Hilgenfeld, R.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European CommissionEuropean Union
CitationJournal: J.Med.Chem. / Year: 2025
Title: Structure-Based Optimization of Pyridone alpha-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.
Authors: Akula, R.K. / El Kilani, H. / Metzen, A. / Roske, J. / Zhang, K. / Gohl, M. / Arisetti, N. / Marsh, G.P. / Maple, H.J. / Cooper, M.S. / Karadogan, B. / Jochmans, D. / Neyts, J. / Rox, K. / ...Authors: Akula, R.K. / El Kilani, H. / Metzen, A. / Roske, J. / Zhang, K. / Gohl, M. / Arisetti, N. / Marsh, G.P. / Maple, H.J. / Cooper, M.S. / Karadogan, B. / Jochmans, D. / Neyts, J. / Rox, K. / Hilgenfeld, R. / Bronstrup, M.
History
DepositionJul 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Jan 29, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: 3C-like proteinase nsp5
BBB: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8626
Polymers66,7002
Non-polymers1,1624
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3010 Å2
ΔGint-38 kcal/mol
Surface area25090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.253, 54.376, 114.192
Angle α, β, γ (deg.)90.000, 101.380, 90.000
Int Tables number4
Space group name H-MP1211

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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: 33350.016 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus
Gene: rep, 1a-1b / Production host: Escherichia coli B (bacteria)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-MJ0 / (2R,3S)-3-[[(2S)-3-cyclopropyl-2-[2-oxidanylidene-3-(3-phenylpropanoylamino)pyridin-1-yl]propanoyl]amino]-N-methyl-2-oxidanyl-4-[(3S)-2-oxidanylidenepyrrolidin-3-yl]butanamide / (S)-3-((S)-3-cyclopropyl-2-(2-oxo-3-(3-phenylpropanamido)pyridin-1(2H)-yl)propanamido)-N-methyl-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)butanamide / RK-90 inhibitor (covalently bound to protein)


Mass: 551.634 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H37N5O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 2.07 Å3/Da / Density % sol: 40.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1MMES pH 6, 0.2MSodium chloride, 20% w/vPEG 6000, 10% v/vEthylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 28, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.519→48.959 Å / Num. obs: 18391 / % possible obs: 98.6 % / Redundancy: 4.9 % / CC1/2: 0.988 / Net I/σ(I): 6.4
Reflection shellResolution: 2.52→2.61 Å / Num. unique obs: 1790 / CC1/2: 0.599

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6y2e

6y2e


Resolution: 2.519→48.959 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.892 / WRfactor Rfree: 0.254 / WRfactor Rwork: 0.179 / SU B: 12.699 / SU ML: 0.271 / Average fsc free: 0.88 / Average fsc work: 0.9155 / Cross valid method: FREE R-VALUE / ESU R Free: 0.361
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2661 950 5.166 %
Rwork0.1856 17441 -
all0.19 --
obs-18391 98.654 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 30.904 Å2
Baniso -1Baniso -2Baniso -3
1--0.181 Å20 Å2-0.062 Å2
2--0.271 Å20 Å2
3----0.061 Å2
Refinement stepCycle: LAST / Resolution: 2.519→48.959 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4662 0 82 72 4816
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134866
X-RAY DIFFRACTIONr_bond_other_d0.0020.0154508
X-RAY DIFFRACTIONr_angle_refined_deg1.6711.6416612
X-RAY DIFFRACTIONr_angle_other_deg1.281.57610358
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.2625603
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.58922.764246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.82515769
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg2.436152
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.281523
X-RAY DIFFRACTIONr_chiral_restr0.0730.2631
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025610
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021164
X-RAY DIFFRACTIONr_nbd_refined0.2150.2992
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1880.24458
X-RAY DIFFRACTIONr_nbtor_refined0.1740.22322
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.22426
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2135
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0460.22
X-RAY DIFFRACTIONr_metal_ion_refined1.0480.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2180.224
X-RAY DIFFRACTIONr_nbd_other0.1810.287
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1570.211
X-RAY DIFFRACTIONr_mcbond_it2.3053.1472415
X-RAY DIFFRACTIONr_mcbond_other2.3053.1472414
X-RAY DIFFRACTIONr_mcangle_it3.6114.7213017
X-RAY DIFFRACTIONr_mcangle_other3.614.7213018
X-RAY DIFFRACTIONr_scbond_it2.7143.4272451
X-RAY DIFFRACTIONr_scbond_other2.7133.4272452
X-RAY DIFFRACTIONr_scangle_it4.2595.0163589
X-RAY DIFFRACTIONr_scangle_other4.2585.0163590
X-RAY DIFFRACTIONr_lrange_it6.13536.8865221
X-RAY DIFFRACTIONr_lrange_other6.13536.8845220
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.519-2.5850.342740.241262X-RAY DIFFRACTION98.2353
2.585-2.6550.338660.2471228X-RAY DIFFRACTION98.9297
2.655-2.7320.389640.2321239X-RAY DIFFRACTION99.694
2.732-2.8160.287750.2251166X-RAY DIFFRACTION98.4921
2.816-2.9090.277620.2091133X-RAY DIFFRACTION99.6664
2.909-3.0110.31540.1941149X-RAY DIFFRACTION98.7685
3.011-3.1240.288540.181038X-RAY DIFFRACTION99.1826
3.124-3.2520.294660.1981046X-RAY DIFFRACTION98.5816
3.252-3.3960.27550.187972X-RAY DIFFRACTION98.0898
3.396-3.5620.248480.178916X-RAY DIFFRACTION94.6955
3.562-3.7540.275440.184914X-RAY DIFFRACTION99.6878
3.754-3.9820.313340.176862X-RAY DIFFRACTION99.5556
3.982-4.2560.23510.158813X-RAY DIFFRACTION99.5392
4.256-4.5970.181440.119761X-RAY DIFFRACTION99.7522
4.597-5.0340.181380.138714X-RAY DIFFRACTION99.4709
5.034-5.6270.231330.187621X-RAY DIFFRACTION99.2413
5.627-6.4950.299350.214557X-RAY DIFFRACTION97.8512
6.495-7.9480.298290.205445X-RAY DIFFRACTION93.8614
7.948-11.2120.153180.15382X-RAY DIFFRACTION99.5025
11.212-48.9590.27160.289223X-RAY DIFFRACTION98.7069

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