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- PDB-9t52: Crystal structure of SARS-CoV-2 Mpro in complex with RK-452 -

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Entry
Database: PDB / ID: 9t52
TitleCrystal structure of SARS-CoV-2 Mpro in complex with RK-452
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Mpro / 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 / snRNP Assembly ...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 / snRNP Assembly / Transcription of SARS-CoV-2 sgRNAs / 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 endosome / host cell endoplasmic reticulum-Golgi intermediate compartment / 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 / G-quadruplex RNA binding / symbiont-mediated suppression of host ISG15-protein conjugation / 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 / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / 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 / proteolysis / DNA-templated transcription / 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: 1.76 Å
AuthorsEl Kilani, H. / Hilgenfeld, R.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European CommissionEuropean Union
CitationJournal: Commun Chem / Year: 2026
Title: Structure-based macrocyclization of alpha-ketoamides leads to potent inhibitors of coronaviral and enteroviral proteases.
Authors: Akula, R.K. / El Kilani, H. / Metzen, A. / Joshi, S. / Durmaz, H. / Veenstra, R. / Roske, J. / Hurdiss, D.L. / Van Kuppeveld, F.J.M. / Rox, K. / Hilgenfeld, R. / Bronstrup, M.
History
DepositionNov 4, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 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 nsp5
B: 3C-like proteinase nsp5
C: 3C-like proteinase nsp5
D: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,4978
Polymers135,3024
Non-polymers2,1954
Water11,403633
1
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7484
Polymers67,6512
Non-polymers1,0972
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint-13 kcal/mol
Surface area24860 Å2
MethodPISA
2
C: 3C-like proteinase nsp5
D: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7484
Polymers67,6512
Non-polymers1,0972
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2990 Å2
ΔGint-10 kcal/mol
Surface area25380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.252, 123.422, 71.582
Angle α, β, γ (deg.)90.000, 104.923, 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: 33825.547 Da / Num. of mol.: 4
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-A1JTT / ~{N}-[(3~{S},6~{S},7~{R},13~{Z})-7-oxidanyl-4,8-bis(oxidanylidene)-6-[[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]methyl]-5,9-diazabicyclo[14.3.1]icosa-1(19),13,16(20),17-tetraen-3-yl]-2-phenyl-ethanamide / RK-452


Mass: 548.673 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H40N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 633 / 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: 2.14 Å3/Da / Density % sol: 42.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M Bis-Tris, pH 6.5, 25% 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: 1.03272 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03272 Å / Relative weight: 1
ReflectionResolution: 1.76→46.05 Å / Num. obs: 110393 / % possible obs: 99.05 % / Redundancy: 14 % / CC1/2: 0.999 / Net I/σ(I): 16.32
Reflection shellResolution: 1.76→1.823 Å / Num. unique obs: 11066 / CC1/2: 0.75

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→46.05 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.958 / SU B: 3.714 / SU ML: 0.109 / Cross valid method: FREE R-VALUE / ESU R: 0.125 / ESU R Free: 0.119
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2126 5651 5.11 %
Rwork0.1741 104926 -
all0.176 --
obs-110393 99.011 %
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: 29.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.532 Å20 Å2-1.693 Å2
2---1.318 Å2-0 Å2
3---2.41 Å2
Refinement stepCycle: LAST / Resolution: 1.76→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9400 0 160 633 10193
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0119786
X-RAY DIFFRACTIONr_bond_other_d0.0010.0169072
X-RAY DIFFRACTIONr_angle_refined_deg1.4041.65913288
X-RAY DIFFRACTIONr_angle_other_deg0.4861.57520848
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.98251212
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.952556
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg3.323512
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.884101542
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg2.244104
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.32410436
X-RAY DIFFRACTIONr_chiral_restr0.070.21488
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211610
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022342
X-RAY DIFFRACTIONr_nbd_refined0.2080.21713
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1950.28702
X-RAY DIFFRACTIONr_nbtor_refined0.1830.24891
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.25171
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2493
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1390.219
X-RAY DIFFRACTIONr_nbd_other0.190.2123
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1620.229
X-RAY DIFFRACTIONr_mcbond_it2.342.9254860
X-RAY DIFFRACTIONr_mcbond_other2.342.9254860
X-RAY DIFFRACTIONr_mcangle_it3.265.2426068
X-RAY DIFFRACTIONr_mcangle_other3.2595.2436069
X-RAY DIFFRACTIONr_scbond_it3.353.3044926
X-RAY DIFFRACTIONr_scbond_other3.353.3054927
X-RAY DIFFRACTIONr_scangle_it5.0685.9057220
X-RAY DIFFRACTIONr_scangle_other5.0685.9067221
X-RAY DIFFRACTIONr_lrange_it6.44131.40510625
X-RAY DIFFRACTIONr_lrange_other6.41431.01910539
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.76-1.8040.3324040.2997754X-RAY DIFFRACTION99.077
1.804-1.8540.3074150.2697550X-RAY DIFFRACTION99.6497
1.854-1.9070.2743960.2517363X-RAY DIFFRACTION99.347
1.907-1.9660.2473560.2297117X-RAY DIFFRACTION98.4715
1.966-2.030.2413380.216663X-RAY DIFFRACTION95.6944
2.03-2.1010.2413560.26760X-RAY DIFFRACTION99.3716
2.101-2.1810.2493710.196471X-RAY DIFFRACTION99.9416
2.181-2.2690.2143660.176193X-RAY DIFFRACTION99.8022
2.269-2.370.2283370.1676011X-RAY DIFFRACTION99.7486
2.37-2.4850.2462980.1735733X-RAY DIFFRACTION99.5543
2.485-2.6190.2312610.1685461X-RAY DIFFRACTION99.5997
2.619-2.7780.2132570.1745130X-RAY DIFFRACTION98.663
2.778-2.9690.2292620.1674692X-RAY DIFFRACTION96.494
2.969-3.2060.1992700.1644527X-RAY DIFFRACTION100
3.206-3.510.1812220.1644183X-RAY DIFFRACTION100
3.51-3.9210.1932150.1573759X-RAY DIFFRACTION99.599
3.921-4.5220.1841730.1383330X-RAY DIFFRACTION99.2351
4.522-5.5260.1791650.1442759X-RAY DIFFRACTION97.3045
5.526-7.7590.2261110.1822205X-RAY DIFFRACTION99.6987
7.759-46.050.152780.161265X-RAY DIFFRACTION100

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