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- PDB-4a1v: Co-Complex structure of NS3-4A protease with the optimized inhibi... -

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Basic information

Entry
Database: PDB / ID: 4a1v
TitleCo-Complex structure of NS3-4A protease with the optimized inhibitory peptide CP5-46A-4D5E
Components
  • CP5-46A-4D5E
  • NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
KeywordsHYDROLASE/PEPTIDE / HYDROLASE-PEPTIDE COMPLEX
Function / homology
Function and homology information


RNA stabilization / DNA/DNA annealing activity / RNA strand annealing activity / RNA folding chaperone / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint ...RNA stabilization / DNA/DNA annealing activity / RNA strand annealing activity / RNA folding chaperone / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / 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 / 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 / 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 / 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. / Trypsin-like serine proteases / 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
: / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS SUBTYPE 1B
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsSchmelz, S. / Kuegler, J. / Collins, J. / Heinz, D.W.
CitationJournal: J.Biol.Chem. / Year: 2012
Title: High Affinity Peptide Inhibitors of the Hepatitis C Virus Ns3-4A Protease Refractory to Common Resistant Mutants.
Authors: Kugler, J. / Schmelz, S. / Gentzsch, J. / Haid, S. / Pollmann, E. / Van Den Heuvel, J. / Franke, R. / Pietschmann, T. / Heinz, D.W. / Collins, J.
History
DepositionSep 20, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 19, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references / Structure summary
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_sheet / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_sheet.number_strands / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
B: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
C: CP5-46A-4D5E
D: CP5-46A-4D5E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,3238
Polymers47,1784
Non-polymers1454
Water1,44180
1
B: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
D: CP5-46A-4D5E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6604
Polymers23,5892
Non-polymers712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2140 Å2
ΔGint-28.2 kcal/mol
Surface area9120 Å2
MethodPISA
2
A: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
C: CP5-46A-4D5E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6634
Polymers23,5892
Non-polymers752
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2110 Å2
ΔGint-21.7 kcal/mol
Surface area9130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.920, 92.920, 82.770
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3 / NS4A / P8 / HEPACIVIRIN / NS3P / P70


Mass: 21385.422 Da / Num. of mol.: 2 / Fragment: RESIDUES 1678-1690,1028-1206
Source method: isolated from a genetically manipulated source
Details: FUSION PROTEIN OF 4A (1678-1690) WITH NS3 (1028-1206)
Source: (gene. exp.) HEPATITIS C VIRUS SUBTYPE 1B / Description: HCV REPLICON I389/NS3-3'UTR (AJ242654) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA2
References: UniProt: P26662, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase
#2: Protein/peptide CP5-46A-4D5E


Mass: 2203.383 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: MUTATED G4D, R5E / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsSEQUENCE DISCREPANCIES HAVE BEEN INDICATED BY AUTHOR AS NATURAL VARIANTS, AS THE REPLICON WAS ...SEQUENCE DISCREPANCIES HAVE BEEN INDICATED BY AUTHOR AS NATURAL VARIANTS, AS THE REPLICON WAS CONSTRUCTED FROM THE CONSENSUS-GENOME OF HCV GENOTYPE 1B.

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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: 2.32 Å3/Da / Density % sol: 46.91 % / Description: NONE
Crystal growDetails: 0.1 M MES PH 6.0 OR 0.1 M NA-CITRATE PH 5.1 AND 2.2M KCL, 5% ISOPROPANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 16, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.2→80.5 Å / Num. obs: 20629 / % possible obs: 99.7 % / Observed criterion σ(I): 2.7 / Redundancy: 4.4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 12.7
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 2.7 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DXP

1dxp


Resolution: 2.2→80.47 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.925 / SU B: 5.559 / SU ML: 0.144 / Cross valid method: THROUGHOUT / ESU R: 0.28 / ESU R Free: 0.215 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT. U VALUES REFINED INDIVIDUALLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.23899 1034 5 %RANDOM
Rwork0.18498 ---
obs0.18773 19595 99.63 %-
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: 33.544 Å2
Baniso -1Baniso -2Baniso -3
1--0.33 Å2-0.17 Å20 Å2
2---0.33 Å20 Å2
3---0.5 Å2
Refinement stepCycle: LAST / Resolution: 2.2→80.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3036 0 4 80 3120
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0193141
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.361.9744286
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5785417
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.28722.364110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.03815483
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0511526
X-RAY DIFFRACTIONr_chiral_restr0.0850.2504
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212360
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_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 76 -
Rwork0.236 1395 -
obs--98.92 %

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