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- PDB-2wrm: Identification of Novel Allosteric Inhibitors of Hepatitis C Viru... -

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Basic information

Entry
Database: PDB / ID: 2wrm
TitleIdentification of Novel Allosteric Inhibitors of Hepatitis C Virus NS5B Polymerase Thumb Domain (Site II) by Structure-Based Design
ComponentsRNA-DIRECTED RNA POLYMERASERNA-dependent RNA polymerase
KeywordsTRANSFERASE / NON-NUCLEOSIDE INHIBITOR / NNI / VIRAL 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 / 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 / virus-mediated perturbation of host defense response / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
: / 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 / 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. / 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-QQ3 / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsDi Marco, S.
CitationJournal: To be Published
Title: Identification of Novel Allosteric Inhibitors of Hepatitis C Virus Ns5B Polymerase Thumb Domain (Site II) by Structure-Based Design
Authors: Di Francesco, M.E. / Di Marco, S. / Summa, V.
History
DepositionSep 1, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 22, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 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_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_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

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Assembly

Deposited unit
A: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6214
Polymers59,6421
Non-polymers9793
Water11,331629
1
A: RNA-DIRECTED RNA POLYMERASE
hetero molecules

A: RNA-DIRECTED RNA POLYMERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,2418
Polymers119,2832
Non-polymers1,9586
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
Buried area2550 Å2
ΔGint-4.2 kcal/mol
Surface area44330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.764, 96.175, 95.683
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-2113-

HOH

21A-2173-

HOH

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Components

#1: Protein RNA-DIRECTED RNA POLYMERASE / RNA-dependent RNA polymerase / P68


Mass: 59641.508 Da / Num. of mol.: 1 / Fragment: NS5B, RESIDUES 2420-2955
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS / Strain: ISOLATE BK / Description: GENBANK ACCESSION NUMBER AB016785 / Variant: GENOTYPE 1B / Plasmid: PT7.7 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-QQ3 / (3R)-3-(4-METHYL-1,3-DIOXO-1,3-DIHYDRO-2H-PYRROLO[3,4-C]QUINOLIN-2-YL)HEXANOIC ACID


Mass: 326.347 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H18N2O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 629 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsNS5B PROTEIN, GENOTYPE 1B AND STRAIN BK, LACKING THE C- TERMINAL 55 AMINO ACIDS. TOTAL AMINO ACIDS ...NS5B PROTEIN, GENOTYPE 1B AND STRAIN BK, LACKING THE C- TERMINAL 55 AMINO ACIDS. TOTAL AMINO ACIDS 535, UNIPROT REFERENCE P26663, 2420-2955

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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: 2.79 Å3/Da / Density % sol: 56 % / Description: NONE
Crystal growpH: 6 / Details: pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. obs: 45650 / % possible obs: 99.6 % / Observed criterion σ(I): 3 / Redundancy: 3.9 % / Biso Wilson estimate: 19.4 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 25
Reflection shellResolution: 1.95→1.98 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 5 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2BRK

2brk


Resolution: 1.95→20 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.912 / SU B: 3.663 / SU ML: 0.106 / Cross valid method: THROUGHOUT / ESU R: 0.164 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. FINAL MODEL ENCOMPASS RESIDUES 1-531, RESIDUES 532- 536 ARE NOT IN DENSITY.
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1840 4.1 %RANDOM
Rwork0.189 ---
obs0.191 43553 99.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 19.26 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20 Å2
2---1.29 Å20 Å2
3---1.16 Å2
Refinement stepCycle: LAST / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4132 0 69 629 4830
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0214143
X-RAY DIFFRACTIONr_bond_other_d0.0150.023687
X-RAY DIFFRACTIONr_angle_refined_deg1.751.975620
X-RAY DIFFRACTIONr_angle_other_deg1.34338490
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3585524
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0820.2630
X-RAY DIFFRACTIONr_gen_planes_refined0.020.024598
X-RAY DIFFRACTIONr_gen_planes_other0.0360.02830
X-RAY DIFFRACTIONr_nbd_refined0.3140.21148
X-RAY DIFFRACTIONr_nbd_other0.2710.24734
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0940.22353
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2250.2467
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1140.210
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2770.272
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2190.240
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6631.52633
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.26724221
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.76531510
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9554.51399
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: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 140 -
Rwork0.271 3175 -
obs--99.4 %

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