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- PDB-4ke5: HCV NS5B GT1B N316Y with GSK5852 -

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Basic information

Entry
Database: PDB / ID: 4ke5
TitleHCV NS5B GT1B N316Y with GSK5852
ComponentsHCV Polymerase
KeywordsREPLICATION/REPLICATION INHIBITOR / HCV Polymerase / HCV NS5B / Site IV Inhibitor / boron / P66 / P70 / RNA directed RNA Polymerase / Polymerase / RNA Replication / 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 / 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 endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / 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 / 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 / host cell plasma membrane / structural molecule activity / 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 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-1PV / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.11 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 25, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2013Provider: repository / Type: Initial release
Revision 1.1May 29, 2013Group: Database references
Revision 1.2Mar 26, 2014Group: Database references
Revision 1.3Feb 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 1.4Mar 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)131,5886
Polymers129,3702
Non-polymers2,2174
Water9,638535
1
A: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7943
Polymers64,6851
Non-polymers1,1092
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7943
Polymers64,6851
Non-polymers1,1092
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.064, 106.855, 126.343
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 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-1PV / [4-({[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1-benzofuran-6-yl](methylsulfonyl)amino}methyl)-2-fluorophenyl]boronic acid / GSK5852


Mass: 554.370 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H25BF2N2O6S / Details: chemically synthesized
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 535 / 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: 2.25 Å3/Da / Density % sol: 45.22 %
Crystal growTemperature: 298 K / 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: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856
DetectorType: RAYONIX MX300HS / Detector: CCD / Date: Mar 6, 2010
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 66142 / % possible obs: 98.7 % / Observed criterion σ(I): 0 / Redundancy: 7 % / Biso Wilson estimate: 19.68 Å2 / Rmerge(I) obs: 0.103 / Net I/σ(I): 5.6
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.428 / % possible all: 88.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.11→29.19 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.927 / Occupancy max: 1 / Occupancy min: 0.4 / SU B: 12.548 / SU ML: 0.149 / SU R Cruickshank DPI: 0.2876 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.288 / ESU R Free: 0.219 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.262 4684 7.1 %RANDOM
Rwork0.22 ---
obs0.223 66073 100 %-
all-66073 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.82 Å2
Baniso -1Baniso -2Baniso -3
1--1.53 Å20 Å20 Å2
2--3.31 Å20 Å2
3----1.78 Å2
Refinement stepCycle: LAST / Resolution: 2.11→29.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8359 0 156 535 9050
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0228776
X-RAY DIFFRACTIONr_bond_other_d0.0010.025843
X-RAY DIFFRACTIONr_angle_refined_deg1.011.98411972
X-RAY DIFFRACTIONr_angle_other_deg0.911314233
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.25651105
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.45722.806335
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.19151405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.6161563
X-RAY DIFFRACTIONr_chiral_restr0.0540.21353
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219758
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021789
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_it0.3551.55507
X-RAY DIFFRACTIONr_mcbond_other0.0581.52206
X-RAY DIFFRACTIONr_mcangle_it0.68528876
X-RAY DIFFRACTIONr_scbond_it0.98333269
X-RAY DIFFRACTIONr_scangle_it1.6594.53082
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.11→2.17 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 280 -
Rwork0.264 3766 -
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)
10.4183-0.15840.46380.1701-0.26811.29050.0422-0.08450.0270.0031-0.03-0.02250.0589-0.0114-0.01220.0181-0.0193-0.00640.0534-0.00750.03811.45645.94147.265
20.46120.11920.28630.16480.22441.05480.02910.11460.023-0.011-0.01810.02330.03880.0277-0.0110.01980.0197-0.00660.05170.00970.0396-11.57545.965-8.007
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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