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- PDB-4dru: HCV NS5B in complex with macrocyclic INDOLE INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 4dru
TitleHCV NS5B in complex with macrocyclic INDOLE INHIBITOR
ComponentsRNA-directed RNA polymerase
KeywordsTransferase/Inhibitor / HCV POLYMERASE / macrocycle inhibitor / thumb domain / Transferase-Inhibitor complex
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 / molecular adaptor activity / 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
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 / : ...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 / 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 / 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
Similarity search - Domain/homology
Chem-0LN / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.1 Å
AuthorsCummings, M.D. / Vendeville, S.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2012
Title: Structure-based macrocyclization yields hepatitis C virus NS5B inhibitors with improved binding affinities and pharmacokinetic properties.
Authors: Cummings, M.D. / Lin, T.I. / Hu, L. / Tahri, A. / McGowan, D. / Amssoms, K. / Last, S. / Devogelaere, B. / Rouan, M.C. / Vijgen, L. / Berke, J.M. / Dehertogh, P. / Fransen, E. / Cleiren, E. ...Authors: Cummings, M.D. / Lin, T.I. / Hu, L. / Tahri, A. / McGowan, D. / Amssoms, K. / Last, S. / Devogelaere, B. / Rouan, M.C. / Vijgen, L. / Berke, J.M. / Dehertogh, P. / Fransen, E. / Cleiren, E. / van der Helm, L. / Fanning, G. / Van Emelen, K. / Nyanguile, O. / Simmen, K. / Raboisson, P. / Vendeville, S.
History
DepositionFeb 17, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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: RNA-directed RNA polymerase
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,91025
Polymers125,2332
Non-polymers2,67623
Water11,277626
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,7768
Polymers62,6171
Non-polymers1,1597
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,13417
Polymers62,6171
Non-polymers1,51716
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.130, 106.643, 133.286
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 RNA-directed RNA polymerase / NS5B / p68


Mass: 62616.723 Da / Num. of mol.: 2 / Fragment: UNP residues 2420-2982
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: HC-J4 / Plasmid: pet21b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2(DE3) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-0LN / 13-cyclohexyl-3-methoxy-17,22-dimethyl-7H-10,6-(methanoiminothioiminobutanoiminomethano)indolo[2,1-a][2]benzazepine-14,23-dione 16,16-dioxide


Mass: 590.733 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H38N4O5S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 626 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.98 Å3/Da / Density % sol: 58.77 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 5.25
Details: 19% PEG 6000, 300mM ammonium sulphate buffer. The NS5b-inhibitor complex was formed by co-crystallization, with the protein solution incubated with ligand for 1 hour prior to preparation of ...Details: 19% PEG 6000, 300mM ammonium sulphate buffer. The NS5b-inhibitor complex was formed by co-crystallization, with the protein solution incubated with ligand for 1 hour prior to preparation of the crystallization drops, pH 5.25, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.978 / Wavelength: 0.978 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.1→83.33 Å / Num. obs: 87966 / % possible obs: 98.8 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Rmerge(I) obs: 0.098
Reflection shellResolution: 2.1→2.23 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.672 / % possible all: 98.5

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 2.1→41.63 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.934 / SU B: 9.858 / SU ML: 0.135 / Cross valid method: THROUGHOUT / ESU R: 0.173 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22557 990 1.1 %RANDOM
Rwork0.18489 ---
obs0.18536 85917 98.86 %-
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: 41.533 Å2
Baniso -1Baniso -2Baniso -3
1-1.77 Å20 Å20 Å2
2---0.46 Å20 Å2
3----1.31 Å2
Refinement stepCycle: LAST / Resolution: 2.1→41.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8632 0 159 626 9417
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0228982
X-RAY DIFFRACTIONr_bond_other_d0.0020.028147
X-RAY DIFFRACTIONr_angle_refined_deg1.3041.9812203
X-RAY DIFFRACTIONr_angle_other_deg0.798318917
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.73751117
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.71122.604361
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.9151495
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1741576
X-RAY DIFFRACTIONr_chiral_restr0.0720.21359
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.029856
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021832
X-RAY DIFFRACTIONr_nbd_refined0.2070.21946
X-RAY DIFFRACTIONr_nbd_other0.1880.28150
X-RAY DIFFRACTIONr_nbtor_refined0.1770.24397
X-RAY DIFFRACTIONr_nbtor_other0.0850.24796
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1460.2533
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1430.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2550.2101
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1660.224
X-RAY DIFFRACTIONr_mcbond_it2.45927197
X-RAY DIFFRACTIONr_mcbond_other0.59822237
X-RAY DIFFRACTIONr_mcangle_it2.95838997
X-RAY DIFFRACTIONr_scbond_it4.60144019
X-RAY DIFFRACTIONr_scangle_it5.90363206
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 70 -
Rwork0.251 6207 -
obs--97.76 %
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)
10.90970.03570.47421.79880.03761.11020.16220.1433-0.455-0.10820.005-0.22080.46540.0958-0.1673-0.0277-0.0064-0.0512-0.1168-0.050.016279.8783.431-11.271
20.0962-0.00590.10890.75780.66461.62450.01710.0151-0.0239-0.0358-0.08710.11090.1379-0.15980.0699-0.20.0051-0.0148-0.14560.0025-0.168627.5537.087-27.074
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 563
2X-RAY DIFFRACTION1A601
3X-RAY DIFFRACTION2B1 - 563

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