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- PDB-2hal: An episulfide cation (thiiranium ring) trapped in the active site... -

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Basic information

Entry
Database: PDB / ID: 2hal
TitleAn episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors
Components
  • Hepatitis A Protease 3C
  • N-ACETYL-LEUCYL-PHENYLALANYL-PHENYLALANYL-GLUTAMATE-FLUOROMETHYLKETONE INHIBITOR
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HEPATITIS A VIRUS / 3C PROTEASE / INHIBITOR DESIGN / METHYLKETONE / EPISULFIDE / PICORNAIN / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


host cell mitochondrial outer membrane / RNA-protein covalent cross-linking / : / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / host multivesicular body / : ...host cell mitochondrial outer membrane / RNA-protein covalent cross-linking / : / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / host multivesicular body / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / RNA helicase activity / membrane => GO:0016020 / symbiont entry into host cell / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane
Similarity search - Function
: / 2B protein soluble domain / Hepatitis A virus, protein VP1-2A / Hepatitis A virus viral protein VP / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid ...: / 2B protein soluble domain / Hepatitis A virus, protein VP1-2A / Hepatitis A virus viral protein VP / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / Trypsin-like serine proteases / Thrombin, subunit H / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
N-acetyl-L-leucyl-L-phenylalanyl-N-[(1S,2R)-1-(2-carboxyethyl)-3-fluoro-2-hydroxypropyl]-L-phenylalaninamide / N-[(BENZYLOXY)CARBONYL]-L-ALANINE / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis A virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsYin, J. / Cherney, M.M. / Bergmann, E.M. / James, M.N.
Citation
Journal: J.Mol.Biol. / Year: 2006
Title: An Episulfide Cation (Thiiranium Ring) Trapped in the Active Site of HAV 3C Proteinase Inactivated by Peptide-based Ketone Inhibitors.
Authors: Yin, J. / Cherney, M.M. / Bergmann, E.M. / Zhang, J. / Huitema, C. / Pettersson, H. / Eltis, L.D. / Vederas, J.C. / James, M.N.
#1: Journal: J.Mol.Biol. / Year: 2005
Title: Dual Modes of Modification of Hepatitis A Virus 3C Protease by a Serine-Derived beta-lactone: Selective Crystallization and formation of a functional catalytic triad in the active site
Authors: Yin, J. / Cherney, M.M. / Bergmann, E.M. / Lall, M.S. / Jain, R.P. / Vederas, J.C. / James, M.N.G.
#2: Journal: VIROLOGY / Year: 1999
Title: Crystal Structure of an Inhibitor Complex of the 3C Proteinase from Hepatitis A Virus (HAV) and Implications for the Polyprotein Processing in HAV
Authors: Bergmann, E.M. / Cherney, M.M. / Mckendrick, J. / Frormann, S. / Luo, C. / Malcolm, B.A. / Vederas, J.C. / James, M.N.
#3: Journal: J.VIROL. / Year: 1997
Title: The Refined Crystal Structure of the 3C Gene Product from Hepatitis A Virus: Specific Proteinase Activity and RNA Recognition
Authors: Bergmann, E.M. / Mosimann, S.C. / Chernaia, M.M. / Malcolm, B.A. / James, M.N.
History
DepositionJun 13, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 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 1.4Aug 30, 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_ref_seq_dif / 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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _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_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatitis A Protease 3C
I: N-ACETYL-LEUCYL-PHENYLALANYL-PHENYLALANYL-GLUTAMATE-FLUOROMETHYLKETONE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,1113
Polymers23,8882
Non-polymers2231
Water7,837435
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1490 Å2
ΔGint-11 kcal/mol
Surface area10090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.584, 56.240, 81.052
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Hepatitis A Protease 3C


Mass: 23288.844 Da / Num. of mol.: 1 / Fragment: 3C proteinase, residues 1520-1731 / Mutation: C24S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis A virus / Genus: Hepatovirus / Gene: 3C / Plasmid: pHAV-3CEX / Production host: Escherichia coli (E. coli) / Strain (production host): D1210
References: UniProt: Q81090, UniProt: P08617*PLUS, picornain 3C
#2: Protein/peptide N-ACETYL-LEUCYL-PHENYLALANYL-PHENYLALANYL-GLUTAMATE-FLUOROMETHYLKETONE INHIBITOR / AC-LFFE-FMK


Type: Peptide-like / Class: Inhibitor / Mass: 598.706 Da / Num. of mol.: 1 / Source method: obtained synthetically
References: N-acetyl-L-leucyl-L-phenylalanyl-N-[(1S,2R)-1-(2-carboxyethyl)-3-fluoro-2-hydroxypropyl]-L-phenylalaninamide
#3: Chemical ChemComp-BBL / N-[(BENZYLOXY)CARBONYL]-L-ALANINE / N-BENZYLOXYCARBONYL-L-SERINE-BETALACTONE


Mass: 223.225 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13NO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 435 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE COORDINATES OF METHYLKETONE GLUTAMATE AND EPISULFIDE METHYLGLUTAMATE ARE ALTERNATE ...THE COORDINATES OF METHYLKETONE GLUTAMATE AND EPISULFIDE METHYLGLUTAMATE ARE ALTERNATE CONFORMATIONS OF THE SAME INHIBITOR. IN THE METHYLKETONE GLUTAMATE CONFORMATION, THE INHIBITOR FORMS ONLY ONE SINGLE COVALENT BOND (FROM ATOM C1) TO SG OF CYS172 (ALTERNATE CONFORMATION B OF CYS172). IN EPISULFIDE METHYLGLUTAMATE CONFORMATION, THE INHIBITOR FORMS TWO COVALENT BONDS (FROM ATOMS C1 AND C, RESPECTIVELY) TO SG OF CYS172 (ALTERNATE CONFORMATION A), LEADING TO THE FORMATION OF AN EPISULFIDE CATION (THIIRANIUM RING).

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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: 2.14 Å3/Da / Density % sol: 42.51 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 2.5% PEG 8000, 1.5% Glycerol, 10mM Tris-HCl, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1159 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 29, 2004
RadiationMonochromator: crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1159 Å / Relative weight: 1
ReflectionResolution: 1.35→40 Å / Num. all: 39555 / Num. obs: 38893 / % possible obs: 85.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.061 / Net I/σ(I): 13
Reflection shellResolution: 1.35→1.4 Å / Rmerge(I) obs: 0.288 / % possible all: 42.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2H6M

2h6m


Resolution: 1.35→20 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.951 / SU B: 1.979 / SU ML: 0.038 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20416 1948 5 %RANDOM
Rwork0.18418 ---
all0.18524 38864 --
obs0.18524 36916 85.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.008 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2---0.11 Å20 Å2
3----0.49 Å2
Refinement stepCycle: LAST / Resolution: 1.35→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1686 0 16 435 2137
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0221726
X-RAY DIFFRACTIONr_angle_refined_deg1.211.9742330
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1035215
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.09324.86172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.47315302
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.513157
X-RAY DIFFRACTIONr_chiral_restr0.0770.2263
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021278
X-RAY DIFFRACTIONr_nbd_refined0.2060.2886
X-RAY DIFFRACTIONr_nbtor_refined0.3050.21195
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1110.2307
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1530.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.257
X-RAY DIFFRACTIONr_mcbond_it4.54881097
X-RAY DIFFRACTIONr_mcangle_it5.372151729
X-RAY DIFFRACTIONr_scbond_it5.65518706
X-RAY DIFFRACTIONr_scangle_it7.08520601
X-RAY DIFFRACTIONr_rigid_bond_restr3.13431803
X-RAY DIFFRACTIONr_sphericity_free5.1113435
X-RAY DIFFRACTIONr_sphericity_bonded5.28931693
LS refinement shellResolution: 1.35→1.385 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 64 -
Rwork0.231 1244 -
obs--39.47 %

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