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- PDB-9f3a: Crystal structure of SARS-CoV-2 Mpro in complex with RK-325 -

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Basic information

Entry
Database: PDB / ID: 9f3a
TitleCrystal structure of SARS-CoV-2 Mpro in complex with RK-325
Components3C-like proteinase nsp5
KeywordsANTIVIRAL PROTEIN / 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) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / 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) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / 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 / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase 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 / SARS-CoV-2 modulates host translation machinery / mRNA (guanine-N7)-methyltransferase / host cell Golgi apparatus / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / forked DNA-dependent helicase activity / single-stranded 3'-5' DNA helicase activity / four-way junction helicase activity / double-stranded DNA helicase 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
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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
DepositionApr 25, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4704
Polymers67,3952
Non-polymers1,0752
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint-12 kcal/mol
Surface area24900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.257, 62.879, 97.495
Angle α, β, γ (deg.)90.000, 94.083, 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: 33697.418 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-A1H9Z / tert-butyl N-[1-[(2S)-3-cyclopropyl-1-[[(2S,3R)-4-(methylamino)-3-oxidanyl-4-oxidanylidene-1-[(3S)-2-oxidanylidenepyrrolidin-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-5-fluoranyl-2-oxidanylidene-pyridin-3-yl]carbamate


Mass: 537.581 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H36FN5O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 2.06 Å3/Da / Density % sol: 40.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Sodium bromide, 0.1 M Bis-Tris propane pH8.5, 20% w/v PEG 3350

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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: Apr 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.15→48.62 Å / Num. obs: 29646 / % possible obs: 99.18 % / Redundancy: 7 % / CC1/2: 0.997 / Net I/σ(I): 6.3
Reflection shellResolution: 2.15→2.227 Å / Num. unique obs: 2952 / CC1/2: 0.559

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→48.62 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.896 / SU B: 9.505 / SU ML: 0.236 / Cross valid method: FREE R-VALUE / ESU R: 0.348 / ESU R Free: 0.254
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2784 1438 4.851 %
Rwork0.2101 28207 -
all0.213 --
obs-29645 99.197 %
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: 34.372 Å2
Baniso -1Baniso -2Baniso -3
1--1.921 Å2-0 Å20.887 Å2
2--1.324 Å20 Å2
3---0.466 Å2
Refinement stepCycle: LAST / Resolution: 2.15→48.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4691 0 76 138 4905
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0114878
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164520
X-RAY DIFFRACTIONr_angle_refined_deg1.4431.6596634
X-RAY DIFFRACTIONr_angle_other_deg0.4731.57610382
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.2095605
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.477528
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg2.63154
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.13510769
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg5.51102
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.69810217
X-RAY DIFFRACTIONr_chiral_restr0.0620.2747
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025782
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021154
X-RAY DIFFRACTIONr_nbd_refined0.2220.21007
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2050.24621
X-RAY DIFFRACTIONr_nbtor_refined0.190.22399
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0870.22636
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2187
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0670.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2380.223
X-RAY DIFFRACTIONr_nbd_other0.1710.257
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1710.27
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0460.21
X-RAY DIFFRACTIONr_mcbond_it2.9093.3592426
X-RAY DIFFRACTIONr_mcbond_other2.9053.3592426
X-RAY DIFFRACTIONr_mcangle_it4.3086.0183029
X-RAY DIFFRACTIONr_mcangle_other4.3086.023030
X-RAY DIFFRACTIONr_scbond_it3.3723.7062452
X-RAY DIFFRACTIONr_scbond_other3.3713.7062453
X-RAY DIFFRACTIONr_scangle_it5.286.6593599
X-RAY DIFFRACTIONr_scangle_other5.2796.6593600
X-RAY DIFFRACTIONr_lrange_it7.2334.0915368
X-RAY DIFFRACTIONr_lrange_other7.23434.115358
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.2060.3251160.3042041X-RAY DIFFRACTION99.8149
2.206-2.2660.331120.2782065X-RAY DIFFRACTION100
2.266-2.3320.3221020.2611943X-RAY DIFFRACTION99.9511
2.332-2.4030.355970.2591935X-RAY DIFFRACTION99.9017
2.403-2.4820.352900.2441852X-RAY DIFFRACTION99.692
2.482-2.5690.356940.2351781X-RAY DIFFRACTION98.9446
2.569-2.6650.326780.2251757X-RAY DIFFRACTION99.3503
2.665-2.7740.335760.2211660X-RAY DIFFRACTION99.5413
2.774-2.8970.276810.2211588X-RAY DIFFRACTION98.6407
2.897-3.0380.305700.2071505X-RAY DIFFRACTION96.3303
3.038-3.2010.357590.2171444X-RAY DIFFRACTION98.622
3.201-3.3940.269750.2081388X-RAY DIFFRACTION99.8635
3.394-3.6280.269780.21299X-RAY DIFFRACTION99.855
3.628-3.9160.234790.1861207X-RAY DIFFRACTION99.8447
3.916-4.2870.239820.1791093X-RAY DIFFRACTION99.5763
4.287-4.7890.198480.1681031X-RAY DIFFRACTION99.5387
4.789-5.5210.222450.175886X-RAY DIFFRACTION96.7775
5.521-6.740.302260.201739X-RAY DIFFRACTION96.1055
6.74-9.4420.231160.171627X-RAY DIFFRACTION99.6899
9.442-48.620.27140.213366X-RAY DIFFRACTION99.7375

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