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- PDB-7xar: Crystal structure of 3C-like protease from SARS-CoV-2 in complex ... -

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Basic information

Entry
Database: PDB / ID: 7xar
TitleCrystal structure of 3C-like protease from SARS-CoV-2 in complex with covalent inhibitor
Components3C-like proteinase
KeywordsVIRAL PROTEIN / 3C-like proteinase / Main protease / SARS-CoV-2 / Chlorofluoroacetamides / Targeted covalent inhibitor
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / endonuclease 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 cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / 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 / regulation of autophagy / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / 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 / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 / Trypsin-like serine proteases / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / Thrombin, subunit H / 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 / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-BOV / NICKEL (II) ION / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsCaaveiro, J.M.M. / Ochi, J. / Takahashi, D. / Ueda, T. / Ojida, A.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)2JP20fk0108519 Japan
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease.
Authors: Hirose, Y. / Shindo, N. / Mori, M. / Onitsuka, S. / Isogai, H. / Hamada, R. / Hiramoto, T. / Ochi, J. / Takahashi, D. / Ueda, T. / Caaveiro, J.M.M. / Yoshida, Y. / Ohdo, S. / Matsunaga, N. / ...Authors: Hirose, Y. / Shindo, N. / Mori, M. / Onitsuka, S. / Isogai, H. / Hamada, R. / Hiramoto, T. / Ochi, J. / Takahashi, D. / Ueda, T. / Caaveiro, J.M.M. / Yoshida, Y. / Ohdo, S. / Matsunaga, N. / Toba, S. / Sasaki, M. / Orba, Y. / Sawa, H. / Sato, A. / Kawanishi, E. / Ojida, A.
History
DepositionMar 18, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,94211
Polymers67,6512
Non-polymers1,2919
Water8,395466
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4070 Å2
ΔGint-66 kcal/mol
Surface area24880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.027, 63.362, 102.831
Angle α, β, γ (deg.)90.000, 90.400, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase / main protease


Mass: 33825.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli (E. coli)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-BOV / 4-fluoranyl-~{N}-[(2~{S})-1-[2-(2-fluoranylethanoyl)-2-[[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]methyl]hydrazinyl]-4-methyl-1-oxidanylidene-pentan-2-yl]-1~{H}-indole-2-carboxamide


Mass: 463.478 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H27F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 466 / 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: 45.68 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 8 mM Nickel chloride 80 mM TRIS (pH 8.5) 16% PEG-MME 2,000 20% Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-5A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 28, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→47.1 Å / Num. obs: 79374 / % possible obs: 99.5 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.059 / Net I/σ(I): 18.3
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 7 % / Rmerge(I) obs: 0.883 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3908 / CC1/2: 0.815 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDS20210323data reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Y2E

6y2e


Resolution: 1.6→47.07 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.954 / SU B: 1.826 / SU ML: 0.063 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.088 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2064 3238 4.1 %RANDOM
Rwork0.1732 ---
obs0.1746 76114 99.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 103.11 Å2 / Biso mean: 22.404 Å2 / Biso min: 12.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.53 Å20 Å20.54 Å2
2--1.43 Å20 Å2
3----0.91 Å2
Refinement stepCycle: final / Resolution: 1.6→47.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4736 0 74 473 5283
Biso mean--24.49 30.87 -
Num. residues----612
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134976
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174468
X-RAY DIFFRACTIONr_angle_refined_deg1.5531.666778
X-RAY DIFFRACTIONr_angle_other_deg1.4391.58510384
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3135628
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.24223.158247
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.93315793
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3031523
X-RAY DIFFRACTIONr_chiral_restr0.0780.2644
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025644
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021049
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 244 -
Rwork0.255 5557 -
all-5801 -
obs--98.46 %

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