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- PDB-4b74: Discovery of an allosteric mechanism for the regulation of HCV NS... -

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Entry
Database: PDB / ID: 4b74
TitleDiscovery of an allosteric mechanism for the regulation of HCV NS3 protein function
ComponentsNON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
KeywordsHYDROLASE / HCV / HELICASE-PROTEASE / ALLOSTERIC POCKET / FUSION PROTEIN
Function / homology
Function and homology information


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 / SH3 domain binding / nucleoside-triphosphate phosphatase ...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 / SH3 domain binding / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / 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 / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / ribonucleoprotein complex / 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 / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA Helicase; Chain A, domain 3 / RNA Helicase Chain A , domain 3 / 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, 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 ...RNA Helicase; Chain A, domain 3 / RNA Helicase Chain A , domain 3 / 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, 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 NS2, C-terminal domain / 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 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 zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepatitis C virus, Non-structural protein NS2 / : / NS3 RNA helicase, C-terminal helical domain / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus non-structural 5a protein membrane anchor / 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 / Hepacivirus/Pegivirus NS3 protease domain profile. / Hepatitis C virus NS3 protease / 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 / P-loop containing nucleotide triphosphate hydrolases / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-1LH / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsSaalau-Bethell, S.M. / Woodhead, A.J. / Chessari, G. / Carr, M.G. / Coyle, J. / Graham, B. / Hiscock, S.D. / Murray, C.W. / Pathuri, P. / Rich, S.J. ...Saalau-Bethell, S.M. / Woodhead, A.J. / Chessari, G. / Carr, M.G. / Coyle, J. / Graham, B. / Hiscock, S.D. / Murray, C.W. / Pathuri, P. / Rich, S.J. / Richardson, C.J. / Williams, P.A. / Jhoti, H.
CitationJournal: Nat.Chem.Biol. / Year: 2012
Title: Discovery of an Allosteric Mechanism for the Regulation of Hcv Ns3 Protein Function
Authors: Saalau-Bethell, S.M. / Woodhead, A.J. / Chessari, G. / Carr, M.G. / Coyle, J. / Graham, B. / Hiscock, S.D. / Murray, C.W. / Pathuri, P. / Rich, S.J. / Richardson, C.J. / Williams, P.A. / Jhoti, H.
History
DepositionAug 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 17, 2012Group: Database references
Revision 1.2Oct 31, 2012Group: Database references
Revision 1.3Nov 14, 2012Group: Database references
Revision 1.4Feb 6, 2013Group: Atomic model
Revision 1.5Dec 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

Downloads & links

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Assembly

Deposited unit
A: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
B: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,5594
Polymers141,7392
Non-polymers8202
Water12,520695
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2800 Å2
ΔGint-9.9 kcal/mol
Surface area50950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.127, 108.429, 139.090
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 70869.391 Da / Num. of mol.: 2 / Fragment: RESIDUES 1678-1690 AND 1029-1657
Source method: isolated from a genetically manipulated source
Details: THE PROTEIN CRYSTALLISED IS A FUSION PROTEIN, COMPRISING A HEXA-HIS TAG, A LINKER REGION, A 11 RESIDUE NS4A COFACTOR PEPTIDE AND THE NS3 PROTEIN
Source: (gene. exp.) HEPATITIS C VIRUS (ISOLATE BK) / Strain: GENOTYPE 1B / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(BE3) / Variant (production host): ROSETTA
References: UniProt: P26663, hepacivirin, nucleoside-triphosphate phosphatase, RNA helicase
#2: Chemical ChemComp-1LH / (2S)-4-[(2-ammonioethyl)amino]-N-[(1R)-1-(4-chloro-2-fluoro-3-phenoxyphenyl)propyl]-4-oxobutan-2-aminium


Mass: 409.925 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H29ClFN3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 695 / 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: 2.2 Å3/Da / Density % sol: 56 % / Description: NONE
Crystal growpH: 6.5
Details: 0.2 M 2-(N-MORPHOLINO)ETHANESULFONIC ACID (MES)-NAOH PH 6.6, 14-20% W/V POLYETHYLENE GLYCOL (PEG) 6000, 10% W/V 2-METHYL-2,4-PENTANDIOL (MPD)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: ADSC CCD / Detector: CCD / Date: Aug 2, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.18→91.1 Å / Num. obs: 71665 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 4.8 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 13.5
Reflection shellResolution: 2.18→2.24 Å / Redundancy: 4 % / Rmerge(I) obs: 0.78 / Mean I/σ(I) obs: 1.7 / % possible all: 90.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
XDSdata reduction
SCALAdata scaling
CSEARCHphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1CU1

1cu1


Resolution: 2.18→62.36 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.921 / SU B: 5.763 / SU ML: 0.148 / Cross valid method: THROUGHOUT / ESU R: 0.241 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24295 3627 5 %RANDOM
Rwork0.17413 ---
obs0.17763 68234 98.71 %-
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: 38.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å20 Å2
2---1.23 Å20 Å2
3---0.42 Å2
Refinement stepCycle: LAST / Resolution: 2.18→62.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9602 0 56 695 10353
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229875
X-RAY DIFFRACTIONr_bond_other_d0.0010.029340
X-RAY DIFFRACTIONr_angle_refined_deg1.4981.96113481
X-RAY DIFFRACTIONr_angle_other_deg0.8242.98921507
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.55451282
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.78322.685368
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.90315.11507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2041566
X-RAY DIFFRACTIONr_chiral_restr0.090.21577
X-RAY DIFFRACTIONr_gen_planes_refined00.02111192
X-RAY DIFFRACTIONr_gen_planes_other00.022162
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: 2.177→2.233 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 226 -
Rwork0.241 4526 -
obs--89.9 %

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