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Basic information

Entry
Database: PDB / ID: 2z3c
TitleA Mechanistic view of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-Like peptidase
Components
  • Replicase polyprotein 1ab (pp1ab)
  • inhibitorEnzyme inhibitor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / beta barrels / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


viral RNA-directed RNA polymerase complex / exoribonuclease complex / viral replication complex formation and maintenance / : / cytoplasmic viral factory / positive regulation of ubiquitin-specific protease activity / symbiont-mediated suppression of host translation / symbiont-mediated suppression of host TRAF-mediated signal transduction => GO:0039527 / endopeptidase complex / endoribonuclease complex ...viral RNA-directed RNA polymerase complex / exoribonuclease complex / viral replication complex formation and maintenance / : / cytoplasmic viral factory / positive regulation of ubiquitin-specific protease activity / symbiont-mediated suppression of host translation / symbiont-mediated suppression of host TRAF-mediated signal transduction => GO:0039527 / endopeptidase complex / endoribonuclease complex / mRNA capping enzyme complex / suppression by virus of host type I interferon production / positive regulation of RNA biosynthetic process / positive stranded viral RNA replication / protein K48-linked deubiquitination / : / : / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / protein K63-linked deubiquitination / 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 / RNA-templated transcription / SARS-CoV-1 modulates host translation machinery / 7-methylguanosine mRNA capping / viral transcription / protein autoprocessing / positive regulation of viral genome replication / DNA helicase activity / Transferases; Transferring one-carbon groups; Methyltransferases / helicase activity / protein processing / SARS-CoV-1 activates/modulates innate immune responses / double-stranded RNA binding / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / ISG15-specific peptidase activity / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endosome / 3'-5'-RNA exonuclease activity / : / host cell endoplasmic reticulum-Golgi intermediate compartment / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / mRNA (nucleoside-2'-O-)-methyltransferase activity / endonuclease activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / DNA helicase / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / host cell cytoplasm / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / membrane => GO:0016020 / host cell perinuclear region of cytoplasm / protein dimerization activity / viral protein processing / lyase activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / symbiont-mediated suppression of host gene expression / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ATP hydrolysis activity / proteolysis / zinc ion binding / ATP binding / membrane / identical protein binding
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / Viral (Superfamily 1) RNA helicase / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / Viral (Superfamily 1) RNA helicase / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2-O-methyltransferase / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 13, 1B domain, coronavirus / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) 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 / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / 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 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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.
Similarity search - Domain/homology
N-acetyl-L-valyl-O-benzyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}propyl]-L-leucinamide / Replicase polyprotein 1ab / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSARS coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsYin, J.
CitationJournal: J.Mol.Biol. / Year: 2007
Title: A mechanistic view of enzyme inhibition and peptide hydrolysis in the active site of the SARS-CoV 3C-like peptidase
Authors: Yin, J. / Niu, C. / Cherney, M.M. / Zhang, J. / Huitema, C. / Eltis, L.D. / Vederas, J.C. / James, M.N.
History
DepositionJun 4, 2007Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 3, 2007Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Dec 25, 2019Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Source and taxonomy
Category: pdbx_distant_solvent_atoms / pdbx_entity_src_syn ...pdbx_distant_solvent_atoms / pdbx_entity_src_syn / reflns_shell / struct_conn / struct_ref_seq / struct_ref_seq_dif
Item: _reflns_shell.pdbx_Rsym_value / _struct_ref_seq.db_align_beg ..._reflns_shell.pdbx_Rsym_value / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq_dif.details
Revision 1.6Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.7Nov 15, 2023Group: Data collection / Derived calculations / Category: chem_comp_atom / chem_comp_bond / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Replicase polyprotein 1ab (pp1ab)
B: inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5713
Polymers34,4782
Non-polymers921
Water5,314295
1
A: Replicase polyprotein 1ab (pp1ab)
B: inhibitor
hetero molecules

A: Replicase polyprotein 1ab (pp1ab)
B: inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1416
Polymers68,9574
Non-polymers1842
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area7110 Å2
ΔGint-38 kcal/mol
Surface area25320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.565, 81.459, 53.359
Angle α, β, γ (deg.)90.00, 104.45, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Replicase polyprotein 1ab (pp1ab) / SARS-CoV 3C-like peptidase


Mass: 33876.637 Da / Num. of mol.: 1
Fragment: UNP residues 3241-3546, SARS-CoV 3C-like peptidase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS coronavirus / Genus: Coronavirus / Gene: rep / Plasmid: PT7HSP2 / Production host: Escherichia coli (E. coli) / Strain (production host): GJ1158
References: UniProt: P59641, UniProt: P0C6X7*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide inhibitor / Enzyme inhibitor


Type: Peptide-like / Class: Inhibitor / Mass: 601.778 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
References: N-acetyl-L-valyl-O-benzyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}propyl]-L-leucinamide
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 295 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE INHIBITOR (CHAIN I) IS A MIXTURE OF A THIOACYL AND EPISULFIDE FORMS. THE UNBOUND FORM OF THE ...THE INHIBITOR (CHAIN I) IS A MIXTURE OF A THIOACYL AND EPISULFIDE FORMS. THE UNBOUND FORM OF THE INHIBITOR CONTAINS A PHTHALHYDRAZIDE GROUP THAT IS LEAVING UPON INHIBITOR BINDING.

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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: 3.34 Å3/Da / Density % sol: 63.17 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 50mM ammonium acetate, 5% polyethylene glycol (Mr10, 000), 3% ethylene glycol, 3% dimethyl sulfoxide, 1mM dithiothreitol, 0.1mM Mes (pH6.5), VAPOR DIFFUSION, HANGING DROP, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 12.3.1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 12, 2006 / Details: crystal
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.79→18.37 Å / Num. all: 42339 / Num. obs: 41831 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 11.6
Reflection shellResolution: 1.79→1.89 Å / Rmerge(I) obs: 0.643 / Mean I/σ(I) obs: 2.7 / Num. unique all: 6186 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
Blu-Icedata collection
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2A5A

2a5a


Resolution: 1.79→18.37 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.951 / SU B: 8.044 / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.108 / ESU R Free: 0.115 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2387 2111 5 %RANDOM
Rwork0.19049 ---
obs0.19285 39711 98.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.492 Å2
Baniso -1Baniso -2Baniso -3
1--2.23 Å20 Å20.91 Å2
2--3.13 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 1.79→18.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2427 0 6 295 2728
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222522
X-RAY DIFFRACTIONr_angle_refined_deg1.71.9653431
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6965313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.16224.234111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45315404
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1531513
X-RAY DIFFRACTIONr_chiral_restr0.1160.2386
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021920
X-RAY DIFFRACTIONr_nbd_refined0.2110.21124
X-RAY DIFFRACTIONr_nbtor_refined0.3130.21716
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1720.2212
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2110.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2330.224
X-RAY DIFFRACTIONr_mcbond_it0.9241.51606
X-RAY DIFFRACTIONr_mcangle_it1.4422539
X-RAY DIFFRACTIONr_scbond_it2.17631030
X-RAY DIFFRACTIONr_scangle_it3.1694.5890
LS refinement shellResolution: 1.79→1.836 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 162 -
Rwork0.298 2888 -
obs--97.38 %

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