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- PDB-4ih7: Hepatitis C Virus polymerase NS5B (BK) with fragment-based compounds -

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Basic information

Entry
Database: PDB / ID: 4ih7
TitleHepatitis C Virus polymerase NS5B (BK) with fragment-based compounds
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Fragment based drug design / TRANSFERASE-TRANSFERASE 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 / 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
3-(3-tert-butylphenyl)pyridin-2(1H)-one / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsHarris, S.F. / Wong, A.
CitationJournal: J.Med.Chem. / Year: 2013
Title: De novo fragment design: a medicinal chemistry approach to fragment-based lead generation.
Authors: Talamas, F.X. / Ao-Ieong, G. / Brameld, K.A. / Chin, E. / de Vicente, J. / Dunn, J.P. / Ghate, M. / Giannetti, A.M. / Harris, S.F. / Labadie, S.S. / Leveque, V. / Li, J. / Lui, A.S. / ...Authors: Talamas, F.X. / Ao-Ieong, G. / Brameld, K.A. / Chin, E. / de Vicente, J. / Dunn, J.P. / Ghate, M. / Giannetti, A.M. / Harris, S.F. / Labadie, S.S. / Leveque, V. / Li, J. / Lui, A.S. / McCaleb, K.L. / Najera, I. / Schoenfeld, R.C. / Wang, B. / Wong, A.
History
DepositionDec 18, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2013Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA-directed RNA polymerase
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,2956
Polymers126,7092
Non-polymers5854
Water6,702372
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6473
Polymers63,3551
Non-polymers2932
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6473
Polymers63,3551
Non-polymers2932
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.254, 104.919, 125.875
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 RNA-directed RNA polymerase / RNA-dependent RNA polymerase / NS5B / p68


Mass: 63354.719 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: Isolate BK / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-1ER / 3-(3-tert-butylphenyl)pyridin-2(1H)-one


Mass: 227.302 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17NO
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 372 / 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: 45.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4.9
Details: 26% PEG 4000, 7.5% glycerol, 50 mM Na Citrate pH 4.9, vapor diffusion, sitting drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 14, 2010
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 52129 / Num. obs: 43111 / % possible obs: 82.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.3 % / Rmerge(I) obs: 0.131 / Χ2: 1.06 / Net I/σ(I): 10.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.382.80.57615741.023130.7
2.38-2.483.10.54623361.082145.4
2.48-2.593.40.46633111.05164.7
2.59-2.734.30.42746111.062189.4
2.73-2.95.30.35951291.077199
2.9-3.125.90.28651541.065199.7
3.12-3.446.10.18551641.027199.5
3.44-3.936.10.11152191.045199.5
3.93-4.956.10.07352211.067199.2
4.95-505.90.06553921.08197.8

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
Blu-Icedata collection
HKL-2000data reduction
BUSTERphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→39.89 Å / Cor.coef. Fo:Fc: 0.8791 / Cor.coef. Fo:Fc free: 0.8484 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.66 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2638 2164 5.04 %RANDOM
Rwork0.2229 ---
all0.2249 52129 --
obs0.2249 42922 83.43 %-
Displacement parametersBiso max: 166.78 Å2 / Biso mean: 40.5143 Å2 / Biso min: 11.02 Å2
Baniso -1Baniso -2Baniso -3
1-6.9469 Å20 Å20 Å2
2---21.2026 Å20 Å2
3---14.2556 Å2
Refine analyzeLuzzati coordinate error obs: 0.347 Å
Refinement stepCycle: LAST / Resolution: 2.3→39.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8680 0 36 372 9088
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3114SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes173HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1360HARMONIC5
X-RAY DIFFRACTIONt_it9013HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1189SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10959SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9013HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg12254HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion17.38
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2858 55 4.81 %
Rwork0.2608 1089 -
all0.262 1144 -
obs--83.43 %

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