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- PDB-4kai: HCV NS5B GT1B N316 with GSK5852A -

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Basic information

Entry
Database: PDB / ID: 4kai
TitleHCV NS5B GT1B N316 with GSK5852A
ComponentsHCV Polymerase
KeywordsREPLICATION/REPLICATION INHIBITOR / HCV Polymerase / HCV NS5B / Site IV Inhibitor / boron / RNA Dependent RNA Polymerase / TRANSFERASE-TRANSFERASE INHIBITOR complex / 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 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 / 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 / MOLECULAR REPLACEMENT / Resolution: 2.3 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 22, 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 1.4Dec 12, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen / pdbx_entity_src_syn
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific
Revision 1.5Feb 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 1.6Mar 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)130,8636
Polymers128,6452
Non-polymers2,2174
Water9,872548
1
A: HCV Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4313
Polymers64,3231
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)65,4313
Polymers64,3231
Non-polymers1,1092
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.708, 107.451, 126.382
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsThe biological unit is a monomer. There are two biological units in the asymmetric unit

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Components

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


Mass: 64322.723 Da / Num. of mol.: 2 / Fragment: HCV NS5B,delta 21 BK, genotype 1b, triple mutant / Mutation: L47Q,F101Y,K114R
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.: 548 / 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: 2.29 Å3/Da / Density % sol: 46.25 %
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: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jan 1, 2010 / Details: MULTILAYER 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
ReflectionRedundancy: 7.2 % / Av σ(I) over netI: 7 / Number: 439785 / Rsym value: 0.105 / D res high: 2.191 Å / D res low: 126.382 Å / Num. obs: 61392 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
6.93126.3899.710.0310.0316.6
4.96.9310010.0560.0567.1
44.910010.0470.0477.2
3.46410010.0590.0597.2
3.13.4610010.0840.0847.2
2.833.110010.1260.1267.3
2.622.8310010.190.197.2
2.452.6210010.2620.2627.2
2.312.4510010.3490.3497.2
2.192.3199.910.4960.4967
ReflectionResolution: 2.191→126.382 Å / Num. obs: 61392 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Rmerge(I) obs: 0.105 / Rsym value: 0.105 / Net I/σ(I): 14.2
Reflection shellResolution: 2.191→2.31 Å / Redundancy: 7 % / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 1.6 / Rsym value: 0.496 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→81.86 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.921 / Occupancy max: 1 / Occupancy min: 0.4 / SU B: 14.274 / SU ML: 0.158 / SU R Cruickshank DPI: 0.3787 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.379 / ESU R Free: 0.239 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.24 2692 5.1 %RANDOM
Rwork0.198 ---
obs0.201 53131 100 %-
all-50439 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.09 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20 Å20 Å2
2--0.86 Å20 Å2
3----1.07 Å2
Refinement stepCycle: LAST / Resolution: 2.3→81.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8389 0 156 548 9093
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228827
X-RAY DIFFRACTIONr_bond_other_d0.0010.025825
X-RAY DIFFRACTIONr_angle_refined_deg0.9681.98112059
X-RAY DIFFRACTIONr_angle_other_deg0.913314195
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.02651121
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.09922.962341
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.149151387
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6181562
X-RAY DIFFRACTIONr_chiral_restr0.0510.21366
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219869
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021805
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_it0.321.55559
X-RAY DIFFRACTIONr_mcbond_other0.0491.52226
X-RAY DIFFRACTIONr_mcangle_it0.62428958
X-RAY DIFFRACTIONr_scbond_it0.91333268
X-RAY DIFFRACTIONr_scangle_it1.5284.53083
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 203 -
Rwork0.234 3657 -
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)
10.5089-0.12260.54090.2729-0.1261.41520.0919-0.07010.02320.0511-0.0499-0.03870.1399-0.0161-0.0420.0425-0.031-0.01120.04290.01030.026611.81546.06946.952
20.64420.0510.34710.32050.11621.11550.0630.1027-0.0407-0.039-0.02720.06140.07250.0195-0.03570.0180.0181-0.01170.0441-0.00060.0272-11.79146.173-7.716
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 564
2X-RAY DIFFRACTION1A601
3X-RAY DIFFRACTION2B1 - 564
4X-RAY DIFFRACTION2B601

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