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- PDB-4kbi: HCV NS5B GT1B N316Y with CMPD 4 -

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Basic information

Entry
Database: PDB / ID: 4kbi
TitleHCV NS5B GT1B N316Y with CMPD 4
ComponentsHCV Polymerase
KeywordsREPLICATION/REPLICATION INHIBITOR / HCV Polymerase / HCV NS5B / Site IV Inhibitor / boron / P66 / P70 / RNA directed RNA Polymerase / tar7360 / Polymerase / 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 / 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 / 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 / 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-1C0 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.06 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)130,5034
Polymers129,3702
Non-polymers1,1332
Water14,862825
1
A: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,2522
Polymers64,6851
Non-polymers5661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,2522
Polymers64,6851
Non-polymers5661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.040, 106.450, 126.490
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-1C0 / 5-cyclopropyl-6-{[(7-fluoro-1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)methyl](methylsulfonyl)amino}-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide


Mass: 566.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H25BF2N2O6S / Details: chemically synthesized
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 825 / 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: 45.06 %
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: Mar 24, 2010 / Details: multi-layer mirror
RadiationMonochromator: multi-layer mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionRedundancy: 6.5 % / Av σ(I) over netI: 20.57 / Number: 348406 / Rmerge(I) obs: 0.104 / Χ2: 1.36 / D res high: 2.25 Å / D res low: 50 Å / Num. obs: 53585 / % possible obs: 97.1
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
6.15099.610.0551.7046.7
4.856.110010.0681.4617.1
4.234.8510010.0631.8287.1
3.854.2310010.0661.6647.2
3.573.8510010.0771.7777.2
3.363.5710010.0831.6167.1
3.193.3610010.1021.4676.9
3.053.1910010.1211.4056.8
2.943.0599.910.1381.3246.6
2.832.9499.810.1531.2556.4
2.752.8399.510.181.2476.2
2.672.7599.110.2011.1936.1
2.62.6797.810.2361.1486
2.532.696.510.2671.1325.9
2.482.5394.810.281.1265.9
2.422.4892.910.321.0536
2.382.4291.210.3421.0556.1
2.332.3890.310.3551.0396.1
2.292.3389.710.3771.0316.1
2.252.2989.710.4691.0786.2
ReflectionResolution: 2.06→40.72 Å / Num. obs: 71514 / % possible obs: 97.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.5 % / Rmerge(I) obs: 0.104 / Rsym value: 0.104 / Net I/σ(I): 7.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.25-2.296.20.469189.7
2.29-2.336.10.377189.7
2.33-2.386.10.355190.3
2.38-2.426.10.342191.2
2.42-2.4860.32192.9
2.48-2.535.90.28194.8
2.53-2.65.90.267196.5
2.6-2.6760.236197.8
2.67-2.756.10.201199.1
2.75-2.836.20.18199.5
2.83-2.946.40.153199.8
2.94-3.056.60.138199.9
3.05-3.196.80.1211100
3.19-3.366.90.1021100
3.36-3.577.10.0831100
3.57-3.857.20.0771100
3.85-4.237.20.0661100
4.23-4.857.10.0631100
4.85-6.17.10.0681100
6.1-506.70.055199.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
JDirectordata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→40.72 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.923 / Occupancy max: 1 / Occupancy min: 0.4 / SU B: 11.839 / SU ML: 0.143 / SU R Cruickshank DPI: 0.2441 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / ESU R: 0.244 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25039 3621 5.1 %RANDOM
Rwork0.21118 ---
obs0.21319 67893 100 %-
all-67893 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 9.693 Å2
Baniso -1Baniso -2Baniso -3
1--0.73 Å20 Å20 Å2
2--1.98 Å20 Å2
3----1.24 Å2
Refinement stepCycle: LAST / Resolution: 2.06→40.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8325 0 80 825 9230
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228682
X-RAY DIFFRACTIONr_bond_other_d0.0010.025776
X-RAY DIFFRACTIONr_angle_refined_deg0.9611.97311843
X-RAY DIFFRACTIONr_angle_other_deg0.917314094
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.07651104
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.42923.047338
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.781151398
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.2951559
X-RAY DIFFRACTIONr_chiral_restr0.0520.21343
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219672
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021753
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3081.55490
X-RAY DIFFRACTIONr_mcbond_other0.0511.52197
X-RAY DIFFRACTIONr_mcangle_it0.59828857
X-RAY DIFFRACTIONr_scbond_it0.91933192
X-RAY DIFFRACTIONr_scangle_it1.5554.52976
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.063→2.116 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 256 -
Rwork0.272 4662 -
obs--100 %
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)
10.4047-0.10480.51410.1626-0.36821.51730.0279-0.06120.02350.0226-0.0197-0.02770.03260.0036-0.00820.0219-0.01070.0020.0186-0.00960.048711.378845.715247.1978
20.4040.07030.39210.17210.32661.41170.01530.10980.0152-0.0348-0.00270.02250.0210.0457-0.01260.02070.00640.00270.03010.00640.0531-11.580245.7021-7.687
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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