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- PDB-4ktc: NS3/NS4A protease with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ktc
TitleNS3/NS4A protease with inhibitor
Components
  • NS4A peptide
  • Serine protease NS3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


RNA stabilization / DNA/DNA annealing activity / RNA folding chaperone / RNA strand annealing activity / 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 ...RNA stabilization / DNA/DNA annealing activity / RNA folding chaperone / RNA strand annealing activity / 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 / protein-DNA complex / 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 / host cell perinuclear region of cytoplasm / RNA helicase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ribonucleoprotein complex / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / chromatin extrusion motor activity / ATP-dependent H2AZ histone chaperone activity / ATP-dependent H3-H4 histone complex chaperone activity / cohesin loader activity / cysteine-type endopeptidase activity / viral RNA genome replication / serine-type endopeptidase activity / DNA clamp loader activity / RNA-directed RNA polymerase 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 / ATP hydrolysis activity / proteolysis / DNA binding / RNA binding / zinc ion binding / ATP 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
(2R,6S,13AR,14AR,16AS)-6-{[(CYCLOPENTYLOXY)CARBONYL]AMINO}-14A-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-5,16-DIOXOOCTADECAHYDROCYCLOPROPA[E]PYRROLO[1,2-A][1,4]DIAZACYCLOPENTADECIN-2-YL 3,4-DIHYDROISOQUINOLINE-2(1H)-CARBOXYLATE / Chem-1X3 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
Synthetic (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhang, H. / Ballard, J. / Vigers, G.P.A. / Brandhuber, B.J.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease.
Authors: Jiang, Y. / Andrews, S.W. / Condroski, K.R. / Buckman, B. / Serebryany, V. / Wenglowsky, S. / Kennedy, A.L. / Madduru, M.R. / Wang, B. / Lyon, M. / Doherty, G.A. / Woodard, B.T. / Lemieux, C. ...Authors: Jiang, Y. / Andrews, S.W. / Condroski, K.R. / Buckman, B. / Serebryany, V. / Wenglowsky, S. / Kennedy, A.L. / Madduru, M.R. / Wang, B. / Lyon, M. / Doherty, G.A. / Woodard, B.T. / Lemieux, C. / Do, M.G. / Zhang, H. / Ballard, J. / Vigers, G. / Brandhuber, B.J. / Stengel, P. / Josey, J.A. / Beigelman, L. / Blatt, L. / Seiwert, S.D.
History
DepositionMay 20, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2014Group: Database references
Revision 1.2Sep 20, 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 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_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

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Assembly

Deposited unit
A: Serine protease NS3
B: NS4A peptide
C: Serine protease NS3
D: NS4A peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,0378
Polymers43,4224
Non-polymers1,6154
Water70339
1
A: Serine protease NS3
B: NS4A peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5184
Polymers21,7112
Non-polymers8072
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-52 kcal/mol
Surface area8400 Å2
MethodPISA
2
C: Serine protease NS3
D: NS4A peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5184
Polymers21,7112
Non-polymers8072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2530 Å2
ΔGint-52 kcal/mol
Surface area8630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.988, 72.988, 127.480
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Serine protease NS3 / Hepacivirin / NS3P / p70


Mass: 20024.881 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus (isolate Japanese) / Production host: Escherichia coli (E. coli)
References: UniProt: P26662, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase
#2: Protein/peptide NS4A peptide


Mass: 1686.097 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Solid-phase peptide synthesis / Source: (synth.) Synthetic (others)
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-1X3 / (2R,6S,13aR,14aR,16aS)-6-{[(cyclopentyloxy)carbonyl]amino}-14a-[(cyclopropylsulfonyl)carbamoyl]-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 3,4-dihydroisoquinoline-2(1H)-carboxylate


Type: Cyclic peptide / Class: Inhibitor / Mass: 741.894 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H51N5O9S
References: (2R,6S,13AR,14AR,16AS)-6-{[(CYCLOPENTYLOXY)CARBONYL]AMINO}-14A-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-5,16-DIOXOOCTADECAHYDROCYCLOPROPA[E]PYRROLO[1,2-A][1,4]DIAZACYCLOPENTADECIN-2-YL 3,4- ...References: (2R,6S,13AR,14AR,16AS)-6-{[(CYCLOPENTYLOXY)CARBONYL]AMINO}-14A-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-5,16-DIOXOOCTADECAHYDROCYCLOPROPA[E]PYRROLO[1,2-A][1,4]DIAZACYCLOPENTADECIN-2-YL 3,4-DIHYDROISOQUINOLINE-2(1H)-CARBOXYLATE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.26 Å3/Da / Density % sol: 45.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 18% PEG3350, 10% Glycerol, 1M MgCl2, 100mM Bis-Tris pH 6.2 and 10mM DTT at 20C. , VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 2, 2005 / Details: Confocal mirrors
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→28.46 Å / Num. all: 17102 / Num. obs: 16946 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.157 / Rsym value: 0.142 / Net I/σ(I): 9.13
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 5.74 % / Rmerge(I) obs: 0.397 / Mean I/σ(I) obs: 2.2 / Num. unique all: 2474 / Rsym value: 0.361 / % possible all: 98.1

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MLPHAREphasing
REFMAC5.7.0029refinement
CrystalCleardata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DY8

1dy8


Resolution: 2.3→28.46 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.919 / SU B: 7.766 / SU ML: 0.191 / Cross valid method: THROUGHOUT / ESU R: 0.395 / ESU R Free: 0.258 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25838 827 4.9 %RANDOM
Rwork0.2064 ---
obs0.20896 16112 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 47.359 Å2
Baniso -1Baniso -2Baniso -3
1-1.08 Å21.08 Å2-0 Å2
2--1.08 Å2-0 Å2
3----3.51 Å2
Refinement stepCycle: LAST / Resolution: 2.3→28.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2778 0 106 39 2923
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192950
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2982.0214030
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2155376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.10921.86891
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.73115447
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8831524
X-RAY DIFFRACTIONr_chiral_restr0.0770.2459
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212122
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.322 59 -
Rwork0.255 1164 -
obs--97.92 %

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