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- PDB-3lox: HCV NS3-4a protease domain with a ketoamide inhibitor derivative ... -

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Basic information

Entry
Database: PDB / ID: 3lox
TitleHCV NS3-4a protease domain with a ketoamide inhibitor derivative of Boceprevir bound
Components
  • HCV NS3 Protease
  • HCV NS4a(21-39) peptide
KeywordsHydrolase/Hydrolase Inhibitor / NS3 Protease Domain / serine protease / ketoamide inhibitor / ATP-binding / Hydrolase / Membrane / Nucleotide-binding / RNA replication / Transmembrane / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / lipid droplet / protein complex oligomerization ...host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / lipid droplet / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ribonucleoprotein complex / induction by virus of host autophagy / viral RNA genome replication / cysteine-type endopeptidase activity / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Thrombin, subunit H - #120 / : / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b ...Thrombin, subunit H - #120 / : / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Trypsin-like serine proteases / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Thrombin, subunit H / 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 / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
(1R,2S,5S)-N-[(2S,3R)-4-AMINO-1-CYCLOBUTYL-3-HYDROXY-4-OXOBUTAN-2-YL]-6,6-DIMETHYL-3-{3-METHYL-N-[(1-METHYLCYCLOHEXYL)CARBAMOYL]-L-VALYL}-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE / BETA-MERCAPTOETHANOL / Chem-MCX / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.65 Å
AuthorsProngay, A.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor.
Authors: Bennett, F. / Huang, Y. / Hendrata, S. / Lovey, R. / Bogen, S.L. / Pan, W. / Guo, Z. / Prongay, A. / Chen, K.X. / Arasappan, A. / Venkatraman, S. / Velazquez, F. / Nair, L. / Sannigrahi, M. ...Authors: Bennett, F. / Huang, Y. / Hendrata, S. / Lovey, R. / Bogen, S.L. / Pan, W. / Guo, Z. / Prongay, A. / Chen, K.X. / Arasappan, A. / Venkatraman, S. / Velazquez, F. / Nair, L. / Sannigrahi, M. / Tong, X. / Pichardo, J. / Cheng, K.C. / Girijavallabhan, V.M. / Saksena, A.K. / Njoroge, F.G.
History
DepositionFeb 4, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 19, 2012Group: Non-polymer description
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _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_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: HCV NS3 Protease
B: HCV NS4a(21-39) peptide
C: HCV NS3 Protease
D: HCV NS4a(21-39) peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0258
Polymers47,2554
Non-polymers7714
Water2,954164
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6940 Å2
ΔGint-125 kcal/mol
Surface area15450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.020, 224.020, 75.240
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ACBD

#1: Protein HCV NS3 Protease


Mass: 21233.225 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Plasmid: pET3a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9ELS8
#2: Protein/peptide HCV NS4a(21-39) peptide


Mass: 2394.039 Da / Num. of mol.: 2 / Source method: obtained synthetically

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Non-polymers , 4 types, 168 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MCX / (1R,2S,5S)-N-[(2S,3R)-4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl]-6,6-dimethyl-3-{3-methyl-N-[(1-methylcyclohexyl)c arbamoyl]-L-valyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide / Boceprevir derivative, bound form


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 561.756 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H51N5O5
References: (1R,2S,5S)-N-[(2S,3R)-4-AMINO-1-CYCLOBUTYL-3-HYDROXY-4-OXOBUTAN-2-YL]-6,6-DIMETHYL-3-{3-METHYL-N-[(1-METHYLCYCLOHEXYL)CARBAMOYL]-L-VALYL}-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE
#5: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O

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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: 3.84 Å3/Da / Density % sol: 68.01 %
Crystal growMethod: vapor diffusion, hanging drop
Details: 4 uL protein solution mixed with 4 uL (0.75-1.00) M NaCl, 0.1 M MES, 0.1 M Na/K PO4, pH 5.6-6.2, suspended over 1 mL reservoir solutions of (1.25-1.50) M NaCl, 0.1 M MES, 0.1 M Na/K PO4, 5 ...Details: 4 uL protein solution mixed with 4 uL (0.75-1.00) M NaCl, 0.1 M MES, 0.1 M Na/K PO4, pH 5.6-6.2, suspended over 1 mL reservoir solutions of (1.25-1.50) M NaCl, 0.1 M MES, 0.1 M Na/K PO4, 5 mM beta-mercaptoethanol, pH 5.6-6.2. The trays were set at 4C for 5-7 days to control nucleation, followed by incubation for 3 weeks at 12C to maximize crystal growth, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Oct 11, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. obs: 21990 / % possible obs: 99 % / Observed criterion σ(I): 1
Reflection shellResolution: 2.65→2.77 Å / Num. unique all: 21990 / % possible all: 99

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Processing

Software
NameVersionClassification
HKL-2000data collection
X-PLORmodel building
X-PLOR98.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB Entry 208M

208m


Resolution: 2.65→8 Å / Isotropic thermal model: Overall / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.273 1823 -Random
Rwork0.19 ---
all-22189 --
obs-18454 83.2 %-
Refinement stepCycle: LAST / Resolution: 2.65→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 46 164 2934
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.008
X-RAY DIFFRACTIONx_angle_d1.903
X-RAY DIFFRACTIONx_improper_angle_d1.306
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs% reflection obs (%)
2.65-2.770.38871920.3043X-RAY DIFFRACTION172076.4
2.77-2.910.35152060.265X-RAY DIFFRACTION189383.5
2.91-3.080.30742100.2428X-RAY DIFFRACTION205490.2
3.08-3.30.29422440.227X-RAY DIFFRACTION211293.8
3.3-3.60.26632280.1955X-RAY DIFFRACTION220296.2
3.6-4.060.23482520.1677X-RAY DIFFRACTION220197.4

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