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- PDB-3kee: HCV NS3/NS4A complexed with Non-covalent macrocyclic compound TMC435 -

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Basic information

Entry
Database: PDB / ID: 3kee
TitleHCV NS3/NS4A complexed with Non-covalent macrocyclic compound TMC435
Components
  • 19-mer peptide from Genome polyprotein
  • Genome polyprotein
KeywordsHYDROLASE / HCV / NS3 / NS4A / macrocycle / noncovalent / TMC435
Function / homology
Function and homology information


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 / host cell mitochondrion / 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 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 / host cell mitochondrion / 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 / 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 / symbiont entry into host cell / ribonucleoprotein complex / induction by virus of host autophagy / virus-mediated perturbation of host defense response / 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 / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / 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 / 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
Chem-30B / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsLindberg, J.D. / Nystrom, S. / Cummings, M.D.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2010
Title: Induced-Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target
Authors: Cummings, M.D. / Lindberg, J.D. / Lin, T.-I. / de Kock, H. / Lenz, O. / Lilja, E. / Fellander, S. / Baraznenok, V. / Nystrom, S. / Nilsson, M. / Vrang, L. / Edlund, M. / Rosenquist, A. / ...Authors: Cummings, M.D. / Lindberg, J.D. / Lin, T.-I. / de Kock, H. / Lenz, O. / Lilja, E. / Fellander, S. / Baraznenok, V. / Nystrom, S. / Nilsson, M. / Vrang, L. / Edlund, M. / Rosenquist, A. / Samuelsson, B. / Raboisson, P. / Simmen, K.
History
DepositionOct 26, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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.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: Genome polyprotein
E: 19-mer peptide from Genome polyprotein
B: Genome polyprotein
F: 19-mer peptide from Genome polyprotein
C: Genome polyprotein
G: 19-mer peptide from Genome polyprotein
D: Genome polyprotein
H: 19-mer peptide from Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,62518
Polymers90,1808
Non-polymers3,44610
Water88349
1
A: Genome polyprotein
E: 19-mer peptide from Genome polyprotein
C: Genome polyprotein
G: 19-mer peptide from Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8139
Polymers45,0904
Non-polymers1,7235
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5910 Å2
ΔGint-109 kcal/mol
Surface area16870 Å2
2
B: Genome polyprotein
F: 19-mer peptide from Genome polyprotein
D: Genome polyprotein
H: 19-mer peptide from Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8139
Polymers45,0904
Non-polymers1,7235
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5950 Å2
ΔGint-107 kcal/mol
Surface area16720 Å2
Unit cell
Length a, b, c (Å)48.034, 54.454, 85.495
Angle α, β, γ (deg.)92.44, 93.16, 116.04
Int Tables number1
Space group name H-MP1

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Components

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Protein / Protein/peptide , 2 types, 8 molecules ABCDEFGH

#1: Protein
Genome polyprotein


Mass: 20150.939 Da / Num. of mol.: 4 / Fragment: NS3 protease domain, UNP residues 1027-1206
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Production host: Escherichia coli (E. coli) / References: UniProt: P90191, hepacivirin
#2: Protein/peptide
19-mer peptide from Genome polyprotein


Mass: 2394.039 Da / Num. of mol.: 4 / Fragment: NS4a peptide, UNP residues 1682-1700 / Source method: obtained synthetically / Details: chemical synthesis / Source: (synth.) Hepatitis C virus / References: UniProt: Q6GYR8

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Non-polymers , 4 types, 59 molecules

#3: Chemical
ChemComp-30B / (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide / Simeprevir


Mass: 749.939 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C38H47N5O7S2 / Comment: medication*YM
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 2.22 Å3/Da / Density % sol: 44.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1M Hepes, 1.9M Ammonium sulphate, 0.35M NaCl, 10% Isopropanol, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9755 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: Jul 11, 2008
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9755 Å / Relative weight: 1
ReflectionResolution: 2.4→48.8 Å / Num. all: 30282 / Num. obs: 29045 / % possible obs: 95.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.2 % / Rmerge(I) obs: 0.151 / Rsym value: 0.151 / Net I/σ(I): 10
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.683 / Mean I/σ(I) obs: 2.1 / Rsym value: 0.683 / % possible all: 95.9

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Processing

Software
NameVersionClassification
DNAdata collection
PHASERphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3KF2

3kf2


Resolution: 2.4→48.8 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.894 / SU B: 9.003 / SU ML: 0.209 / Cross valid method: THROUGHOUT / ESU R: 0.584 / ESU R Free: 0.281 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24607 1461 5 %RANDOM
Rwork0.19625 ---
all0.199 30282 --
obs0.19882 27584 95.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.372 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0.04 Å20.01 Å2
2---0.07 Å20.01 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.4→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5592 0 236 49 5877
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0225940
X-RAY DIFFRACTIONr_angle_refined_deg1.9552.0168104
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.325752
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.98821.875192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.37315916
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.421552
X-RAY DIFFRACTIONr_chiral_restr0.1180.2956
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024356
X-RAY DIFFRACTIONr_nbd_refined0.2330.22384
X-RAY DIFFRACTIONr_nbtor_refined0.3130.23890
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2212
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2830.2105
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2370.26
X-RAY DIFFRACTIONr_mcbond_it0.7751.53841
X-RAY DIFFRACTIONr_mcangle_it1.3326064
X-RAY DIFFRACTIONr_scbond_it2.00432472
X-RAY DIFFRACTIONr_scangle_it3.1774.52016
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 98 -
Rwork0.261 2013 -
obs--96.17 %

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