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- PDB-8y4e: Crystal structure of SARS main protease in complex with Bofutrelvir -

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Basic information

Entry
Database: PDB / ID: 8y4e
TitleCrystal structure of SARS main protease in complex with Bofutrelvir
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication ...Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication / methyltransferase activity / SARS-CoV-1 activates/modulates innate immune responses / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 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 cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / host cell Golgi apparatus / methylation / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / RNA-directed RNA polymerase activity / proteolysis / zinc ion binding / identical protein binding / membrane
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / 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 ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / 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 / 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. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
~{N}-[(2~{S})-3-cyclohexyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]propan-2-yl]-1~{H}-indole-2-carboxamide / Chem-FHR / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsLin, C. / Wang, W.W. / Zhang, J. / Li, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Crystal structure of SARS main protease in complex with Bofutrelvir
Authors: Lin, C. / Wang, W.W. / Zhang, J. / Li, J.
History
DepositionJan 30, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 8, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)67,0394
Polymers66,1342
Non-polymers9052
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2040 Å2
ΔGint-9 kcal/mol
Surface area24000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.008, 59.787, 67.836
Angle α, β, γ (deg.)91.952, 102.776, 108.403
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,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: 33066.754 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome-related coronavirus
Gene: 1a / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0C6U8, SARS coronavirus main proteinase
#2: Chemical ChemComp-FHR / ~{N}-[(2~{S})-3-cyclohexyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]propan-2-yl]-1~{H}-indole-2-carboxamide


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 452.546 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N4O4 / Feature type: SUBJECT OF INVESTIGATION
References: ~{N}-[(2~{S})-3-cyclohexyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]propan-2-yl]-1~{H}-indole-2-carboxamide
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / 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: 3.1 Å3/Da / Density % sol: 60.35 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 0.1M Hepes pH7.5, 15% PEG8000, 10% Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.979191 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979191 Å / Relative weight: 1
ReflectionResolution: 2.04→65.74 Å / Num. obs: 49399 / % possible obs: 97.6 % / Redundancy: 3 % / Biso Wilson estimate: 32.0230947469 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 8.9
Reflection shellResolution: 2.04→2.09 Å / Rmerge(I) obs: 0.318 / Num. unique obs: 3589

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PHENIX1.12_2829refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7CA8

7ca8


Resolution: 2.04→26.82 Å / SU ML: 0.272542831473 / Cross valid method: FREE R-VALUE / σ(F): 1.97340568875 / Phase error: 32.3745863981
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.273941421456 2375 4.81763966084 %
Rwork0.238197115643 46923 -
obs0.239932071284 49298 97.4731097754 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.9174705953 Å2
Refinement stepCycle: LAST / Resolution: 2.04→26.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4382 0 66 162 4610
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007999296852514556
X-RAY DIFFRACTIONf_angle_d1.025906446886218
X-RAY DIFFRACTIONf_chiral_restr0.0549241319847720
X-RAY DIFFRACTIONf_plane_restr0.0069389403401802
X-RAY DIFFRACTIONf_dihedral_angle_d7.087243487432624
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.04-2.08170.3236938825791080.3112304655432735X-RAY DIFFRACTION96.2749746021
2.0817-2.12690.2919950513831210.2889761268462753X-RAY DIFFRACTION96.0882647944
2.1269-2.17640.3552954206211380.2849320946872718X-RAY DIFFRACTION96.0322797579
2.1764-2.23080.3497851818341480.2727719919012724X-RAY DIFFRACTION96.5702757229
2.2308-2.2910.3313185972991390.2668985771172767X-RAY DIFFRACTION96.8666666667
2.291-2.35840.2938013293671450.2760248122412710X-RAY DIFFRACTION96.8781812012
2.3584-2.43450.3035841686161410.2831159826422730X-RAY DIFFRACTION96.8296795953
2.4345-2.52140.3670943305981370.281733067962765X-RAY DIFFRACTION97.3498825897
2.5214-2.62230.3164942009591490.2773264831282772X-RAY DIFFRACTION97.3991330443
2.6223-2.74150.3501546590041460.2825241320682759X-RAY DIFFRACTION97.7785257489
2.7415-2.88590.3021639780831460.2776588681922747X-RAY DIFFRACTION97.835644234
2.8859-3.06650.3552219016631430.2688541996772778X-RAY DIFFRACTION97.7904251758
3.0665-3.30290.2418785391361450.2513881474942765X-RAY DIFFRACTION98.4771573604
3.3029-3.63450.2708615577781490.2413898014962777X-RAY DIFFRACTION98.3529411765
3.6345-4.15880.229275735681460.2093460081372800X-RAY DIFFRACTION98.7927565392
4.1588-5.23320.2146265562721450.180060206092820X-RAY DIFFRACTION99.1638795987
5.2332-26.820.2375427154291290.1982886610052803X-RAY DIFFRACTION98.7870619946

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