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Basic information

Entry
Database: PDB / ID: 2z3e
TitleA Mechanistic view of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-Like peptidase
Components
  • ACE VAL Z3E LEU KCQ peptide
  • Replicase polyprotein 1ab (pp1ab)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SARS / 3C-like peptidase / 3CL / main proteinase / viral cysteine protease / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / VIRAL PROTEIN
Function / homology
Function and homology information


viral RNA-directed RNA polymerase complex / viral replication complex formation and maintenance / exoribonuclease complex / symbiont-mediated suppression of host TRAF-mediated signal transduction => GO:0039527 / : / : / : / cytoplasmic viral factory / positive regulation of ubiquitin-specific protease activity / symbiont-mediated suppression of host translation ...viral RNA-directed RNA polymerase complex / viral replication complex formation and maintenance / exoribonuclease complex / symbiont-mediated suppression of host TRAF-mediated signal transduction => GO:0039527 / : / : / : / cytoplasmic viral factory / positive regulation of ubiquitin-specific protease activity / symbiont-mediated suppression of host translation / : / : / endopeptidase complex / endoribonuclease complex / mRNA capping enzyme complex / positive stranded viral RNA replication / positive regulation of RNA biosynthetic process / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / protein K48-linked deubiquitination / 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 / protein K63-linked deubiquitination / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / RNA-templated transcription / viral transcription / SARS-CoV-1 modulates host translation machinery / protein autoprocessing / 7-methylguanosine mRNA capping / membrane => GO:0016020 / 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 / 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 / endonuclease activity / 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 / host cell cytoplasm / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / protein dimerization activity / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / RNA helicase / 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 / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / ATP hydrolysis activity / proteolysis / zinc ion binding / ATP binding / identical protein binding / membrane
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 / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus ...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 / 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 / : / 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 / 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
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
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 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 1.3Feb 27, 2013Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Nov 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_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 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)
I: ACE VAL Z3E LEU KCQ peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6614
Polymers34,4762
Non-polymers1842
Water3,729207
1
A: Replicase polyprotein 1ab (pp1ab)
I: ACE VAL Z3E LEU KCQ peptide
hetero molecules

A: Replicase polyprotein 1ab (pp1ab)
I: ACE VAL Z3E LEU KCQ peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,3218
Polymers68,9534
Non-polymers3684
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
2


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6630 Å2
ΔGint-31 kcal/mol
Surface area25640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.264, 82.235, 53.487
Angle α, β, γ (deg.)90.00, 104.45, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-966-

HOH

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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 ACE VAL Z3E LEU KCQ peptide


Type: Peptide-like / Class: Inhibitor / Mass: 599.762 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: The peptide was chemically synthesized.
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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 207 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE PEPTIDE INHIBITOR REPRESENTS THE THIACYL-LIKE FORM OF THE INHIBITOR. THE ORIGINAL INHIBITOR HAD ...THE PEPTIDE INHIBITOR REPRESENTS THE THIACYL-LIKE FORM OF THE INHIBITOR. THE ORIGINAL INHIBITOR HAD A LARGE LEAVING GROUP (PHTALHYDRAZIDE) THAT IS REMOVED DURING THE REACTION SO IS NOT INCLUDED IN THE LIGAND.

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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: 3.37 Å3/Da / Density % sol: 63.5 %
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: May 5, 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: 2.32→15.47 Å / Num. all: 19683 / Num. obs: 18207 / % possible obs: 92.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.061 / Rsym value: 0.061 / Net I/σ(I): 8.9
Reflection shellResolution: 2.32→2.45 Å / Rmerge(I) obs: 0.186 / Mean I/σ(I) obs: 5.4 / Num. unique all: 2868 / Rsym value: 0.186 / % possible all: 92.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
Blu-Icedata collection
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2A5A

2a5a


Resolution: 2.32→15.47 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.894 / SU B: 13.202 / SU ML: 0.173 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.311 / ESU R Free: 0.253 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23123 872 5 %RANDOM
Rwork0.18746 ---
obs0.18952 16658 89.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.661 Å2
Baniso -1Baniso -2Baniso -3
1--1.67 Å20 Å21.37 Å2
2--2.61 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 2.32→15.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2415 0 12 207 2634
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0222524
X-RAY DIFFRACTIONr_angle_refined_deg1.9561.9683431
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4125313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.77724.182110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.53415403
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.941513
X-RAY DIFFRACTIONr_chiral_restr0.1270.2384
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021916
X-RAY DIFFRACTIONr_nbd_refined0.2290.21129
X-RAY DIFFRACTIONr_nbtor_refined0.3080.21652
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2170.2121
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2620.254
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2570.210
X-RAY DIFFRACTIONr_mcbond_it0.8311.51602
X-RAY DIFFRACTIONr_mcangle_it1.3222537
X-RAY DIFFRACTIONr_scbond_it2.1731034
X-RAY DIFFRACTIONr_scangle_it3.1284.5892
LS refinement shellResolution: 2.32→2.379 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 59 -
Rwork0.234 1090 -
obs-1149 81.26 %

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