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- PDB-3lon: HCV NS3-4a protease domain with ketoamide inhibitor narlaprevir -

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Basic information

Entry
Database: PDB / ID: 3lon
TitleHCV NS3-4a protease domain with ketoamide inhibitor narlaprevir
Components
  • Genome polyprotein
  • KK-NS4a(21-39)-KK
KeywordsVIRAL PROTEIN/INHIBITOR / HEPATITIS C VIRUS / NS3 PROTEASE DOMAIN / SERINE PROTEASE / MACROCYCLIC KETOAMIDE INHIBITOR / HYDROLASE / ATP-binding / Capsid protein / Envelope protein / Helicase / Host membrane / Membrane / Nucleotide-binding / RNA replication / Transmembrane / Virion / VIRAL PROTEIN / VIRAL PROTEIN-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 / : ...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 / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / induction by virus of host autophagy / ribonucleoprotein complex / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / 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 / Hepatitis C virus, Core protein, N-terminal ...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 / 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
BETA-MERCAPTOETHANOL / Chem-NNA / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsProngay, A.J.
CitationJournal: To be Published
Title: Candidate selection and preclinical evaluation culminating in the discovery of Narlaprevir (SCH 900518): A potent, selective and orally efficacious second generation HCV NS3 serine protease inhibitor
Authors: Arasappan, A. / Bennett, F. / Bogen, S.L. / Blackman, M. / Chen, K. / Hendrata, S. / Huang, Y. / Huelgas, R.M. / Nair, L. / Padilla, A.I. / Pan, W. / Pike, R. / Pinto, P. / Ruan, S. / ...Authors: Arasappan, A. / Bennett, F. / Bogen, S.L. / Blackman, M. / Chen, K. / Hendrata, S. / Huang, Y. / Huelgas, R.M. / Nair, L. / Padilla, A.I. / Pan, W. / Pike, R. / Pinto, P. / Ruan, S. / Sannigrahi, M. / Velaquez, F. / Vibulbhan, B. / Wu, W. / Yang, W. / Saksena, A.K. / Girijavallabhan, V. / Shih, N.Y. / Kong, J. / Meng, T. / Jin, Y. / Wong, J. / McNamara, P. / Prongay, A. / Madison, V. / Piwinski, J.J. / Cheng, K.C. / Morrison, R. / Malcolm, B. / Tong, X. / Ralston, R. / Njoroge, F.G.
History
DepositionFeb 4, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 14, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / pdbx_struct_conn_angle ...chem_comp / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _pdbx_struct_conn_angle.ptnr1_auth_comp_id ..._chem_comp.pdbx_synonyms / _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.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 1.3Oct 13, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.4Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Genome polyprotein
B: KK-NS4a(21-39)-KK
C: Genome polyprotein
D: KK-NS4a(21-39)-KK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,1738
Polymers47,2554
Non-polymers9194
Water3,999222
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6970 Å2
ΔGint-123 kcal/mol
Surface area15440 Å2
MethodPISA
2
A: Genome polyprotein
B: KK-NS4a(21-39)-KK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,4815
Polymers23,6272
Non-polymers8543
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2990 Å2
ΔGint-54 kcal/mol
Surface area9900 Å2
MethodPISA
3
C: Genome polyprotein
D: KK-NS4a(21-39)-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 area1690 Å2
ΔGint-46 kcal/mol
Surface area7820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.392, 224.392, 75.331
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 Genome polyprotein


Mass: 21233.225 Da / Num. of mol.: 2 / Fragment: UNP residues 1027 to 1207
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
#2: Protein/peptide KK-NS4a(21-39)-KK


Mass: 2394.039 Da / Num. of mol.: 2 / Mutation: C32S / Source method: obtained synthetically
Details: PEPTIDES WERE SYNTHESIZED USING FMOC SOLID-PHASE CHEMISTRY ON AN ABI 431 SYNTHESIZER (FOSTER CITY,CA). PRELOADED 2-CHLOROTRITYL CHLORIDE RESIN OR WANG RESIN USED FOR THE SOLID PHASE ASSEMBLY ...Details: PEPTIDES WERE SYNTHESIZED USING FMOC SOLID-PHASE CHEMISTRY ON AN ABI 431 SYNTHESIZER (FOSTER CITY,CA). PRELOADED 2-CHLOROTRITYL CHLORIDE RESIN OR WANG RESIN USED FOR THE SOLID PHASE ASSEMBLY OF NS4A ACTIVATOR PEPTIDE. THE SEQUENCE OF THE PEPTIDE WAS LYS-LYS-GLY-SER-VAL-VAL-ILE-VAL-GLY-ARG-ILE-VAL-LEU-SER-GLY-LYS-PRO-ALA-ILE-VAL-PRO-LYS-LYS-OH. TRIFUNCTIONAL RESIDUE SIDECHAIN PROTECTING GROUPS INCLUDED TERT-BUTYL FOR SER, TERT-BUTOXYCARBONYL FOR LYS, AND 2,2,4,6,7--5-SULFONYL FOR ARG. CLEAVAGE AND SIDECHAIN DEPROTECTION WAS ACCOMPLISHED USING 92.5% TRIFLUOROACETIC ACID, WITH 2.5% EACH OF WATER, ETHANEDITHIOL AND TRIISOPROPYLSILANE FOR 2 HOURS. THE PEPTIDE WAS PURIFIED BY REVERSED PHASE HPLC. THE PEPTIDE MOLECULAR WEIGHT WAS CONFIRMED BY ELECTROSPRAY IONIZATION MASS SPECTROMETRY.

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Non-polymers , 4 types, 226 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NNA / (1R,2S,5S)-3-[N-({1-[(tert-butylsulfonyl)methyl]cyclohexyl}carbamoyl)-3-methyl-L-valyl]-N-{(1S)-1-[(1R)-2-(cyclopropylamino)-1-hydroxy-2-oxoethyl]pentyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide / Narlaprevir, bound form / Narlaprevir


Mass: 709.980 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H63N5O7S / Comment: medication, antivirus, inhibitor*YM
#5: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


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


Mass: 18.015 Da / Num. of mol.: 222 / 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: 3.86 Å3/Da / Density % sol: 68.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: Crystallization was performed by the vapor diffusion method using hanging drops (4 L protein solution mixed with 4 L (0.75 - 1.00) M NaCl - 0.1 M MES - 0.1 M Na/K PO4, pH 5.6 - 6.2) ...Details: Crystallization was performed by the vapor diffusion method using hanging drops (4 L protein solution mixed with 4 L (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 -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, temperature 277K

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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: Apr 15, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 36700 / Num. obs: 32304 / % possible obs: 88 % / Observed criterion σ(I): 1 / Redundancy: 9.2 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 24.9
Reflection shellResolution: 2.2→2.24 Å / Rmerge(I) obs: 0.633 / Mean I/σ(I) obs: 1.26 / Rsym value: 0.381 / % possible all: 24.8

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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: 2.2→8 Å / Isotropic thermal model: Overall / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.269 2906 -Random
Rwork0.204 ---
all-31502 --
obs-29169 92.6 %-
Refinement stepCycle: LAST / Resolution: 2.2→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 55 222 3001
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg1.942
X-RAY DIFFRACTIONx_improper_angle_d1.248
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs% reflection obs (%)
2.2-2.30.3842850.4007X-RAY DIFFRACTION96422
2.3-2.420.38432320.3554X-RAY DIFFRACTION244155
2.42-2.560.35054070.3107X-RAY DIFFRACTION374884
2.56-2.750.30344210.2811X-RAY DIFFRACTION418594
2.75-3.020.2744400.2326X-RAY DIFFRACTION436797
3.02-3.420.26914390.2052X-RAY DIFFRACTION4435100

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