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- PDB-5eu8: Structure of FIPV main protease in complex with dual inhibitors -

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Basic information

Entry
Database: PDB / ID: 5eu8
TitleStructure of FIPV main protease in complex with dual inhibitors
Components
  • N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
  • main protease3C-like protease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / FIPV / main protease / dual inhibitors / zinc / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


RNA exonuclease activity / host cell membrane / endoplasmic reticulum-Golgi intermediate compartment / DNA helicase activity / viral genome replication / methyltransferase activity / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / methylation / 3'-5'-RNA exonuclease activity ...RNA exonuclease activity / host cell membrane / endoplasmic reticulum-Golgi intermediate compartment / DNA helicase activity / viral genome replication / methyltransferase activity / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / methylation / 3'-5'-RNA exonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / mRNA guanylyltransferase / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methyltransferase cap1 / 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 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / membrane => GO:0016020 / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Alphacoronavirus nsp1 / Replicase polyprotein N-term from Coronavirus nsp1 / Alphacoronavirus nsp1 domain superfamily / : / Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain ...Alphacoronavirus nsp1 / Replicase polyprotein N-term from Coronavirus nsp1 / Alphacoronavirus nsp1 domain superfamily / : / Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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. / Coronavirus 3Ecto domain profile. / 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal
Similarity search - Domain/homology
N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE / Replicase polyprotein 1ab / 3C-like proteinase
Similarity search - Component
Biological speciesFeline infectious peritonitis virus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.447 Å
AuthorsWang, F. / Chen, C. / Liu, X. / Yang, K. / Xu, X. / Yang, H.
Funding support China, 3items
OrganizationGrant numberCountry
National Key Basic Research Program of China (973 program)2015CB859800 China
National Natural Science Foundation of China31300150 China
Tianjin Marine Science and Technology ProgramKJXH2014-16 China
CitationJournal: J.Virol. / Year: 2015
Title: Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors
Authors: Wang, F. / Chen, C. / Liu, X. / Yang, K. / Xu, X. / Yang, H.
History
DepositionNov 18, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2016Group: Database references
Revision 1.2Nov 8, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list / struct_conn / struct_conn_type / struct_site
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.conn_type_id / _struct_conn.id / _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_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: main protease
B: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3054
Polymers34,1782
Non-polymers1272
Water1,982110
1
A: main protease
B: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
hetero molecules

A: main protease
B: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6108
Polymers68,3554
Non-polymers2554
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area4800 Å2
ΔGint-105 kcal/mol
Surface area26190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)112.261, 112.261, 102.102
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11A-532-

HOH

21A-590-

HOH

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Components

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


Mass: 33496.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Feline infectious peritonitis virus / Gene: 1b, ORF1a / Plasmid: pGEX-6P-1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: V9PIT1, UniProt: Q98VG9*PLUS
#2: Protein/peptide N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE


Type: Peptide-like / Class: Inhibitor / Mass: 680.791 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
References: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 110 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.43 Å3/Da / Density % sol: 49.5 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2 M zinc acetate dihydrate, 0.1 M sodium cacodylate trihydrate, 14%(w/v) polyethylene glycol 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97923 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 11, 2014
RadiationMonochromator: DCM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97923 Å / Relative weight: 1
ReflectionResolution: 2.447→42.94 Å / Num. obs: 12082 / % possible obs: 97.8 % / Redundancy: 7.4 % / Biso Wilson estimate: 43.61 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 31.15
Reflection shellResolution: 2.447→2.535 Å / Mean I/σ(I) obs: 8.6 / % possible all: 99.09

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
SCALEPACKdata reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2AMP

2amp


Resolution: 2.447→42.938 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.243 589 4.88 %Random selection
Rwork0.2115 ---
obs0.2131 12061 97.57 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.4 Å2
Refinement stepCycle: LAST / Resolution: 2.447→42.938 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2350 0 5 110 2465
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092403
X-RAY DIFFRACTIONf_angle_d1.1713253
X-RAY DIFFRACTIONf_dihedral_angle_d14.669849
X-RAY DIFFRACTIONf_chiral_restr0.044360
X-RAY DIFFRACTIONf_plane_restr0.005419
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4473-2.69350.32981480.24722868X-RAY DIFFRACTION99
2.6935-3.08320.2981480.24642851X-RAY DIFFRACTION99
3.0832-3.88410.22911430.20872851X-RAY DIFFRACTION98
3.8841-42.94450.21731500.19462902X-RAY DIFFRACTION95
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.18030.37950.7462.21980.62361.6916-0.06960.06110.1775-0.189-0.03190.1765-0.1945-0.06170.00010.38780.0179-0.02620.31010.01930.3852-33.4962-14.9306-10.8463
20.9641-0.130.07160.739-0.44481.1004-0.04960.1790.0481-0.1585-0.0440.21080.40090.030100.52330.009-0.04460.41790.01780.4285-37.3906-48.022-16.5915
30.2612-0.1732-0.14120.53920.23170.1196-0.3073-0.03550.0230.00880.2116-0.05760.04010.1071-0.00040.4113-0.01040.03580.47230.00580.4185-33.4766-43.7898-6.9226
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1Chain A and (RESSEQ 0:188)A0 - 188
2X-RAY DIFFRACTION2Chain A and (RESSEQ 189:270)A189 - 270
3X-RAY DIFFRACTION3Chain A and (RESSEQ 271:299)A271 - 299

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