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- PDB-3hhk: HCV NS5b polymerase complex with a substituted benzothiadizine -

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Basic information

Entry
Database: PDB / ID: 3hhk
TitleHCV NS5b polymerase complex with a substituted benzothiadizine
ComponentsHCV NS5 polymerase
KeywordsHYDROLASE/HYDROLASE Inhibitor / NS5b / polymerase / HCV / inhhibitor / ATP-binding / Envelope protein / Helicase / Hydrolase / Membrane / Nucleotide-binding / RNA replication / Transmembrane / HYDROLASE-HYDROLASE Inhibitor COMPLEX
Function / homology
Function and homology information


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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity ...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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity / monoatomic ion transmembrane transport / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / 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 / induction by virus of host autophagy / ribonucleoprotein complex / 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 / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
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 / : ...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. / Reverse transcriptase/Diguanylate cyclase domain / DEAD box, Flavivirus / Flavivirus DEAD 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 / Reverse transcriptase/Diguanylate cyclase domain / Alpha-Beta Plaits / 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 / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-77Z / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1b
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsConcha, N.O. / Singh, O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase.
Authors: Shaw, A.N. / Tedesco, R. / Bambal, R. / Chai, D. / Concha, N.O. / Darcy, M.G. / Dhanak, D. / Duffy, K.J. / Fitch, D.M. / Gates, A. / Johnston, V.K. / Keenan, R.M. / Lin-Goerke, J. / Liu, N. ...Authors: Shaw, A.N. / Tedesco, R. / Bambal, R. / Chai, D. / Concha, N.O. / Darcy, M.G. / Dhanak, D. / Duffy, K.J. / Fitch, D.M. / Gates, A. / Johnston, V.K. / Keenan, R.M. / Lin-Goerke, J. / Liu, N. / Sarisky, R.T. / Wiggall, K.J. / Zimmerman, M.N.
History
DepositionMay 15, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 1, 2017Group: Advisory / Refinement description
Category: pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / software
Item: _software.name
Revision 1.3Feb 21, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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Assembly

Deposited unit
A: HCV NS5 polymerase
B: HCV NS5 polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,8424
Polymers124,8692
Non-polymers9732
Water8,521473
1
A: HCV NS5 polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9212
Polymers62,4351
Non-polymers4871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV NS5 polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9212
Polymers62,4351
Non-polymers4871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.740, 107.442, 126.807
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 HCV NS5 polymerase


Mass: 62434.551 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: Q99AU2
#2: Chemical ChemComp-77Z / 2-({(3R)-3-[(3S)-1-(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl]-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl}oxy)acetamide


Mass: 486.541 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N4O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 473 / 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: 2.34 Å3/Da / Density % sol: 47.41 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: micro seeding requied, chnage from pH 5.5 to 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM1A / Wavelength: 1 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→81.92 Å / Num. obs: 112795 / % possible obs: 87 % / Observed criterion σ(F): 112795 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.066 / Rsym value: 0.066 / Net I/σ(I): 11.3

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Processing

Software
NameVersionClassificationNB
REFMAC5refinement
PDB_EXTRACT3.005data extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→81.92 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.922 / Occupancy max: 1 / Occupancy min: 0 / SU B: 4.606 / SU ML: 0.079 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.133 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24962 5679 5 %RANDOM
Rwork0.22886 ---
obs0.22989 107086 87.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.834 Å2
Baniso -1Baniso -2Baniso -3
1-0.42 Å20 Å20 Å2
2--0.34 Å20 Å2
3----0.76 Å2
Refinement stepCycle: LAST / Resolution: 1.7→81.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8748 0 68 473 9289
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0229006
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9391.97412236
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.62551126
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.24722.853361
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.153151523
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.7721570
X-RAY DIFFRACTIONr_chiral_restr0.0590.21373
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026824
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1750.24325
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2910.26275
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0950.2558
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1760.260
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0950.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3121.55811
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.54329083
X-RAY DIFFRACTIONr_scbond_it0.73433751
X-RAY DIFFRACTIONr_scangle_it1.194.53152
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.745 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 388 -
Rwork0.256 7599 -
obs--85.57 %
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)
10.4509-0.16970.17370.2233-0.07850.6870.0258-0.03180.02240.0105-0.0106-0.0349-0.00230.0092-0.0153-0.0418-0.013-0.0024-0.0453-0.0124-0.049597.12246.62450.032
20.32240.03390.21080.26330.06680.61390.00460.0470.0310.0002-0.01020.0052-0.01080.03780.0056-0.04740.01690.0072-0.03240.01-0.052274.17846.251-5.713
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 563
2X-RAY DIFFRACTION2B1 - 563

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