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- PDB-1w3c: Crystal structure of the Hepatitis C Virus NS3 Protease in comple... -

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Basic information

Entry
Database: PDB / ID: 1w3c
TitleCrystal structure of the Hepatitis C Virus NS3 Protease in complex with a peptidomimetic inhibitor
Components
  • NONSTRUCTURAL PROTEIN NS4A (P4)
  • PROTEASE/HELICASE NS3 (P70)
KeywordsHYDROLASE / SERINE PROTEASE / HCV / INDOLINE-BASED PEPTIDOMIMETIC INHIBITOR
Function / homology
Function and homology information


RNA stabilization / RNA folding chaperone / DNA/DNA annealing activity / RNA strand annealing activity / hepacivirin / 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 ...RNA stabilization / RNA folding chaperone / DNA/DNA annealing activity / RNA strand annealing activity / hepacivirin / 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 / protein-DNA complex / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / DNA binding / RNA binding / zinc ion binding / ATP binding / membrane
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 / helicase superfamily c-terminal 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-DN1 / Chem-DN2 / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsDi Marco, S. / Volpari, C.
Citation
Journal: J.Med.Chem. / Year: 2004
Title: The Design and Enzyme-Bound Crystal Structure of Indoline Based Peptidomimetic Inhibitors of Hepatitis C Virus Ns3 Protease
Authors: Ontoria, J.M. / Di Marco, S. / Conte, I. / Di Francesco, M.E. / Gardelli, C. / Koch, U. / Matassa, V.G. / Poma, M. / Steinkuhler, C. / Volpari, C. / Harper, S.
#1: Journal: J.Biol.Chem. / Year: 2000
Title: Inhibition of the Hepatitis C Virus Ns3-4A Protease. The Crystal Structures of Two Protease- Inhibitor Complexes
Authors: Di Marco, S. / Rizzi, M. / Volpari, C. / Walsh, M. / Narjes, F. / Colarusso, S. / De Francesco, R. / Matassa, V.G. / Sollazzo, M.
History
DepositionJul 14, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2004Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2015Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" AND "BB" IN EACH CHAIN ON SHEET ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" AND "BB" IN EACH CHAIN ON SHEET RECORDS BELOW ARE ACTUALLY 6-STRANDED BARRELS 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: PROTEASE/HELICASE NS3 (P70)
B: PROTEASE/HELICASE NS3 (P70)
C: NONSTRUCTURAL PROTEIN NS4A (P4)
D: NONSTRUCTURAL PROTEIN NS4A (P4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0076
Polymers42,8714
Non-polymers1,1352
Water3,531196
1
A: PROTEASE/HELICASE NS3 (P70)
C: NONSTRUCTURAL PROTEIN NS4A (P4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0033
Polymers21,4362
Non-polymers5681
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3040 Å2
ΔGint-12 kcal/mol
Surface area8320 Å2
MethodPISA
2
B: PROTEASE/HELICASE NS3 (P70)
D: NONSTRUCTURAL PROTEIN NS4A (P4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0033
Polymers21,4362
Non-polymers5681
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3040 Å2
ΔGint-13.1 kcal/mol
Surface area8370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.411, 92.411, 80.007
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 PROTEASE/HELICASE NS3 (P70)


Mass: 19749.553 Da / Num. of mol.: 2 / Fragment: PROTEASE, RESIDUES 305-491
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS (ISOLATE 1) / Description: EXPRESSED UNDER T7 PROMOTER, IPTG INDUCED / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: Q81755, UniProt: P26662*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide NONSTRUCTURAL PROTEIN NS4A (P4)


Mass: 1686.097 Da / Num. of mol.: 2 / Fragment: RESIDUES 956-967 / Mutation: YES / Source method: obtained synthetically / Source: (synth.) HEPATITIS C VIRUS (ISOLATE 1) / References: UniProt: Q81755, UniProt: P26662*PLUS
#3: Chemical ChemComp-DN1 / 3-({(2S)-2-[({(1R)-1-[({(1R)-1-[(R)-CARBOXY(HYDROXY)METHYL]-3,3-DIFLUOROPROPYL}AMINO)CARBONYL]-3-METHYLBUTYL}AMINO)CARB ONYL]-2,3-DIHYDRO-1H-INDOL-2-YL}METHYL)THIOPHENE-2-CARBOXYLIC ACID / PEPTIDOMIMETIC INHIBITOR


Mass: 567.602 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31F2N3O7S
#4: Chemical ChemComp-DN2 / 3-({(2S)-2-[({(1S)-1-[({(1S)-1-[(R)-CARBOXY(HYDROXY)METHYL]-3,3-DIFLUOROPROPYL}AMINO)CARBONYL]-3-METHYLBUTYL}AMINO)CARBONYL]-2,3-DIHYDRO-1H-INDOL-2-YL}METHYL)THIOPHENE-2-CARBOXYLIC ACID / PEPTIDOMIMETIC INHIBITOR


Mass: 567.602 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31F2N3O7S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 196 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED MUTATION IN CHAINS C, D THR 955 TO LYS ENGINEERED MUTATION IN CHAINS C, D PRO 970 TO LYS
Sequence detailsENGINEERED MUTATIONS IN CHAINS C AND D WERE INTRODUCED TO INCREASE THE SOLUBILITY OF THE PEPTIDE

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.36 Å3/Da / Density % sol: 47.42 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.934
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. obs: 16243 / % possible obs: 93.7 % / Observed criterion σ(I): 3 / Redundancy: 2.77 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 15.7
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 3 / % possible all: 95

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Processing

Software
NameVersionClassification
REFMAC5.1refinement
DENZOdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DXP

1dxp


Resolution: 2.3→20 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflection
Rfree0.24 -5 %
Rwork0.177 --
obs-15517 89.5 %
Displacement parametersBiso mean: 51.15 Å2
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2714 0 78 196 2988

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