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- PDB-3kn2: HCV NS3 Protease Domain with ketoamide inhibitor -

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Basic information

Entry
Database: PDB / ID: 3kn2
TitleHCV NS3 Protease Domain with ketoamide inhibitor
Components
  • HCV NS3 Protease Domain
  • Peptide KK-NS4A-KK
KeywordsHYDROLASE / Hepatitis C Virus / NS3 Protease Domain / serine protease / ketoamide inhibitor / ATP-binding / Capsid protein / Envelope protein / Helicase / Host membrane / Membrane / Nucleotide-binding / RNA replication / Transmembrane / Virion
Function / homology
Function and homology information


positive stranded viral RNA replication / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / symbiont-mediated transformation of host cell / 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 / viral genome replication ...positive stranded viral RNA replication / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / symbiont-mediated transformation of host cell / 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 / viral genome replication / ribonucleoside triphosphate phosphatase activity / SH3 domain binding / nucleoside-triphosphate phosphatase / channel activity / viral nucleocapsid / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ribonucleoprotein complex / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / protein-containing complex / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / identical protein binding / membrane
Similarity search - Function
Thrombin, subunit H - #120 / 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 core protein, chain A superfamily ...Thrombin, subunit H - #120 / 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 core protein, chain A superfamily / : / 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 / NS3 RNA helicase, C-terminal helical domain / 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 / 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 / Trypsin-like serine proteases / 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
Chem-M66 / Genome polyprotein / Genome polyprotein / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsNair, L.G. / Sannigrahi, M. / Pinto, P. / Bogen, S. / Chen, K.X. / Njoroge, G. / Prongay, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.
Authors: Nair, L.G. / Sannigrahi, M. / Bogen, S. / Pinto, P. / Chen, K.X. / Prongay, A. / Tong, X. / Cheng, K.C. / Girijavallabhan, V. / George Njoroge, F.
History
DepositionNov 11, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_conn_type / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _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_type.id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 27, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HCV NS3 Protease Domain
B: Peptide KK-NS4A-KK
C: HCV NS3 Protease Domain
D: Peptide KK-NS4A-KK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,1047
Polymers47,2554
Non-polymers8503
Water3,567198
1
C: HCV NS3 Protease Domain
D: Peptide KK-NS4A-KK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6933
Polymers23,6272
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-47 kcal/mol
Surface area7820 Å2
MethodPISA
2
A: HCV NS3 Protease Domain
B: Peptide KK-NS4A-KK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,4124
Polymers23,6272
Non-polymers7842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2670 Å2
ΔGint-52 kcal/mol
Surface area10050 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6650 Å2
ΔGint-122 kcal/mol
Surface area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.486, 224.486, 75.465
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

#1: Protein HCV NS3 Protease Domain


Mass: 21233.225 Da / Num. of mol.: 2 / Fragment: UNP residues 1027-1207 / Mutation: Q1145R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Strain: H77 Strain of genotype 1a / Gene: NS3 / Production host: Escherichia coli (E. coli) / Strain (production host): bl21(de3) / References: UniProt: Q9ELS8, UniProt: P26664*PLUS
#2: Protein/peptide Peptide KK-NS4A-KK


Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: UNP residues 1676-1698 / Mutation: T1676K, T1677K, D1697K, D1698K / Source method: obtained synthetically / Details: Synthesized using Fmoc solid-phase chemistry / References: UniProt: Q9QP61, UniProt: Q9WMX2*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-M66 / (1R,2S,5S)-3-{(2S)-2-(2,3-dihydro-1H-inden-2-yl)-2-[({(1S)-2,2-dimethyl-1-[(2-oxopiperidin-1-yl)methyl]propyl}carbamoyl)amino]acetyl}-6,6-dimethyl-N-{(1S)-1-[oxo(prop-2-en-1-ylamino)acetyl]butyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide


Mass: 718.925 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H58N6O6
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.87 Å3/Da / Density % sol: 68.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 1.25-1.50 M NaCl, 0.1 M MES, 0.1 M Na/K PO4, 5 mM b-mercaptoethanol, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Temp details: 277 then 285

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 4, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 33010 / Num. obs: 31312 / % possible obs: 94 % / Observed criterion σ(I): 3

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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 / Resolution: 2.3→35.18 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.264 2776 -random
Rwork0.2 ---
all-33010 --
obs-27856 89 %-
Refinement stepCycle: LAST / Resolution: 2.3→35.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 54 198 2976
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.008
X-RAY DIFFRACTIONx_angle_deg1.928
X-RAY DIFFRACTIONx_improper_angle_d1.472
LS refinement shellResolution: 2.3→2.4 Å
RfactorNum. reflection% reflection
Rfree0.3418 285 -
Rwork0.2993 --
obs-2603 79.78 %

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