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- PDB-4kb7: HCV NS5B GT1B N316Y with CMPD 32 -

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Basic information

Entry
Database: PDB / ID: 4kb7
TitleHCV NS5B GT1B N316Y with CMPD 32
ComponentsHCV Polymerase
KeywordsREPLICATION/REPLICATION INHIBITOR / HCV Polymerase / HCV NS5B / Site IV Inhibitor / boron / P66 / P70 / RNA directed RNA Polymerase / tar7360 / RNA-dependent RNA polymerase / REPLICATION-REPLICATION 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 / : ...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 / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / ribonucleoprotein complex / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / 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 non-structural protein NS4b ...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 / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Alpha-Beta Plaits / Peptidase S1, PA clan, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-690 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsWilliams, S.P. / Kahler, K.M. / Shotwell, J.B.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase.
Authors: Maynard, A. / Crosby, R.M. / Ellis, B. / Hamatake, R. / Hong, Z. / Johns, B.A. / Kahler, K.M. / Koble, C. / Leivers, A. / Leivers, M.R. / Mathis, A. / Peat, A.J. / Pouliot, J.J. / Roberts, C. ...Authors: Maynard, A. / Crosby, R.M. / Ellis, B. / Hamatake, R. / Hong, Z. / Johns, B.A. / Kahler, K.M. / Koble, C. / Leivers, A. / Leivers, M.R. / Mathis, A. / Peat, A.J. / Pouliot, J.J. / Roberts, C.D. / Samano, V. / Schmidt, R.M. / Smith, G.K. / Spaltenstein, A. / Stewart, E.L. / Thommes, P. / Turner, E.M. / Voitenleitner, C. / Walker, J.T. / Waitt, G. / Weatherhead, J. / Weaver, K. / Williams, S. / Wright, L. / Xiong, Z.Z. / Haigh, D. / Shotwell, J.B.
History
DepositionApr 23, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2013Provider: repository / Type: Initial release
Revision 1.1May 15, 2013Group: Other
Revision 1.2May 29, 2013Group: Database references
Revision 1.3Mar 26, 2014Group: Database references
Revision 1.4Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HCV Polymerase
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,4954
Polymers129,3702
Non-polymers1,1252
Water14,772820
1
A: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,2482
Polymers64,6851
Non-polymers5621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,2482
Polymers64,6851
Non-polymers5621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.031, 106.616, 126.515
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein HCV Polymerase / RNA-directed RNA polymerase / NS5B / p68


Mass: 64685.145 Da / Num. of mol.: 2 / Fragment: HCV Polymerase 1-572 / Mutation: L47Q, F101Y, K114R, N316Y
Source method: isolated from a genetically manipulated source
Details: C-terminal 6xHis tag / Source: (gene. exp.) Hepatitis C virus / Strain: genotype 1B / Gene: NS5B / Plasmid: pET21 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-690 / 5-cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3R)-1-hydroxy-1,3-dihydro-2,1-benzoxaborol-3-yl]ethyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide


Mass: 562.417 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28BFN2O6S / Details: chemically synthesized
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 820 / 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: 2.24 Å3/Da / Density % sol: 45.15 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1M citrate pH5.0, 17% PEG4000, 10% glycerol, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jan 1, 2010 / Details: multi-layer mirrors
RadiationMonochromator: multi-layer mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.811→126.515 Å / Num. all: 95243 / Num. obs: 95243 / % possible obs: 89.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.2 % / Rmerge(I) obs: 0.069 / Rsym value: 0.069 / Net I/σ(I): 15.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.811-1.912.70.4481.82166280250.44852.6
1.91-2.023.90.2972.743034111450.29777.1
2.02-2.165.80.223.677522133300.2297.5
2.16-2.3470.1714.690062127770.171100
2.34-2.567.20.1236.384382117750.123100
2.56-2.867.20.0878.876957106980.087100
2.86-3.317.20.05812.86870394950.058100
3.31-4.057.10.0416.95751480550.0499.9
4.05-5.737.10.03617.54502463140.036100
5.73-126.5156.80.03119.52456736290.03199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
JDirectordata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→81.53 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.871 / WRfactor Rfree: 0.2117 / WRfactor Rwork: 0.1834 / Occupancy max: 1 / Occupancy min: 0.4 / FOM work R set: 0.8101 / SU B: 7.358 / SU ML: 0.099 / SU R Cruickshank DPI: 0.1742 / SU Rfree: 0.1524 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.174 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2412 4626 5 %RANDOM
Rwork0.2085 ---
all0.2101 95243 --
obs0.2101 92221 92.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 80.3 Å2 / Biso mean: 18.733 Å2 / Biso min: 2.49 Å2
Baniso -1Baniso -2Baniso -3
1--0.54 Å20 Å20 Å2
2--1.11 Å20 Å2
3----0.57 Å2
Refinement stepCycle: LAST / Resolution: 1.85→81.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8362 0 80 820 9262
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0228762
X-RAY DIFFRACTIONr_bond_other_d0.0010.025844
X-RAY DIFFRACTIONr_angle_refined_deg1.0171.97211962
X-RAY DIFFRACTIONr_angle_other_deg0.957314264
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.78951128
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.46723.032343
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.19151420
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.7221561
X-RAY DIFFRACTIONr_chiral_restr0.0510.21367
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0219782
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021799
X-RAY DIFFRACTIONr_mcbond_it0.2711.55537
X-RAY DIFFRACTIONr_mcbond_other0.0381.52218
X-RAY DIFFRACTIONr_mcangle_it0.52328942
X-RAY DIFFRACTIONr_scbond_it0.73933225
X-RAY DIFFRACTIONr_scangle_it1.2434.53000
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 203 -
Rwork0.329 3892 -
all-4095 -
obs--56.27 %
Refinement TLS params.

T11: 0.0255 Å2 / 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 °)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.3259-0.07240.24320.1719-0.17210.83970.0381-0.06610.01950.0088-0.0308-0.01480.0336-0.0083-0.0073-0.012-0.0020.0538-0.00710.041111.31745.76347.059
20.44910.0770.24890.15870.17690.91950.03980.1056-0.0109-0.0142-0.00690.01130.04470.0697-0.03290.0201-0.0080.0565-0.00020.0497-11.56745.832-7.524
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 563
2X-RAY DIFFRACTION1A601
3X-RAY DIFFRACTION2B1 - 562
4X-RAY DIFFRACTION2B601

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