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- PDB-5fpy: Structure of hepatitis C virus (HCV) full-length NS3 complex with... -

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Basic information

Entry
Database: PDB / ID: 5fpy
TitleStructure of hepatitis C virus (HCV) full-length NS3 complex with small-molecule ligand 5-bromo-1-methyl-1H-indole-2-carboxylic acid (AT21457) in an alternate binding site.
ComponentsSERINE PROTEASE NS3
KeywordsHYDROLASE / HEPATITIS C VIRUS / HCV / NS3 COMPLEX / PROTEASE-HELICASE / PROTEIN-LIGAND COMPLEX / FRAGMENT SCREENING / ALTERNATE BINDING SITE / AT21457.
Function / homology
Function and homology information


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 / SH3 domain binding / nucleoside-triphosphate phosphatase ...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 / SH3 domain binding / 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 / 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, 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 ...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, 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 / 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 / P-loop containing nucleotide triphosphate hydrolases / 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
5-bromo-1-methyl-1H-indole-2-carboxylic acid / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsDavies, T.G. / Jhoti, H. / Ludlow, R.F. / Saini, H.K. / Tickle, I.J. / Verdonk, M.
Citation
Journal: Proc.Natl.Acad.Sci.USA / Year: 2015
Title: Detection of Secondary Binding Sites in Proteins Using Fragment Screening.
Authors: Ludlow, R.F. / Verdonk, M.L. / Saini, H.K. / Tickle, I.J. / Jhoti, H.
#1: Journal: Structure / Year: 1999
Title: Molecular Views of Viral Polyprotein Processing Revealed by the Crystal Structure of the Hepatitis C Virus Bifunctional Protease-Helicase.
Authors: Yao, N. / Reichert, P. / Taremi, S.S. / Prosise, W.W. / Weber, P.C.
#2: Journal: 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
DepositionDec 3, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: 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 "AC" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" 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 "BC" 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: SERINE PROTEASE NS3
B: SERINE PROTEASE NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,2474
Polymers141,7392
Non-polymers5082
Water13,115728
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-10.8 kcal/mol
Surface area50820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.902, 109.773, 142.004
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.91357, 0.40632, -0.01705), (0.40667, 0.91303, -0.03154), (0.00275, -0.03575, -0.99936)
Vector: 40.619, -10.025, -80.331)

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Components

#1: Protein SERINE PROTEASE NS3 / HEPACIVIRIN / NS3P / P70


Mass: 70869.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS (ISOLATE BK) / Strain: GENOTYPE 1B / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria)
References: UniProt: P26663, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Chemical ChemComp-R2N / 5-bromo-1-methyl-1H-indole-2-carboxylic acid


Mass: 254.080 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H8BrNO2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 728 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details5-BROMO-1-METHYL-1H-INDOLE-2-CARBOXYLIC ACID (R2N): ASTEX COMPOUND REGISTRY AT21457.
Sequence detailsN-TERM HIS TAG (37). DELETION 1-2. DELETION 632-686.

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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: 2.63 Å3/Da / Density % sol: 52.94 % / Description: NONE
Crystal growpH: 6.6
Details: 0.2M MES/NAOH, 14% W/V PEG 6000, 10% V/V MPD. PROTEIN CONC. = 6 MG/ML., pH 6.6

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 17, 2009 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.52→47 Å / Num. obs: 52097 / % possible obs: 96.3 % / Observed criterion σ(I): -3.7 / Redundancy: 2.7 % / Biso Wilson estimate: 52.63 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 5.4
Reflection shellResolution: 2.52→2.59 Å / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.2 / % possible all: 97.4

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
MOSFLMdata reduction
SCALAdata scaling
CSEARCHphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 5FPS

5fps


Resolution: 2.52→46.99 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.89 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.558 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.82 / SU Rfree Blow DPI: 0.293 / SU Rfree Cruickshank DPI: 0.288
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY DISORDERED REGIONS WERE DELETED. THERE'S ALSO A HINT OF THE LIGAND PARALLEL-STACKING WITH TRP A501 BUT ...Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY DISORDERED REGIONS WERE DELETED. THERE'S ALSO A HINT OF THE LIGAND PARALLEL-STACKING WITH TRP A501 BUT DENSITY IS NOT SUFFICIENTLY GOOD TO BE CERTAIN.
RfactorNum. reflection% reflectionSelection details
Rfree0.241 2354 5.1 %RANDOM
Rwork0.163 ---
obs0.166 46396 95.3 %-
Displacement parametersBiso mean: 46.83 Å2
Baniso -1Baniso -2Baniso -3
1-14.2762 Å20 Å20 Å2
2---5.3851 Å20 Å2
3----8.8911 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 2.52→46.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9416 0 28 728 10172
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0119674HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1213249HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3067SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes158HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1545HARMONIC16
X-RAY DIFFRACTIONt_it9674HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.6
X-RAY DIFFRACTIONt_other_torsion18.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1345SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact11518SEMIHARMONIC4
LS refinement shellResolution: 2.52→2.58 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 178 5.17 %
Rwork0.214 3262 -
all0.22 3440 -
obs--96.63 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.2222-0.1861-0.48470.8246-0.20440.78110.1353-0.04060.1828-0.00950.031-0.0191-0.1075-0.0605-0.1662-0.15470.00660.0514-0.1549-0.0241-0.02465.319615.1134-31.6625
20.97110.0191-0.24960.43120.08541.1171-0.0271-0.0554-0.00660.02240.0327-0.0711-0.06330.205-0.0055-0.1759-0.03860.0523-0.1009-0.0105-0.01142.33917.0493-49.5155
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|705 - A|631 }
2X-RAY DIFFRACTION2{ B|705 - B|631 }

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