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- PDB-3lkh: Inhibitors of Hepatitis C Virus Polymerase: Synthesis and Charact... -

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Basic information

Entry
Database: PDB / ID: 3lkh
TitleInhibitors of Hepatitis C Virus Polymerase: Synthesis and Characterization of Novel 6-Fluoro-N-[2-Hydroxy-1(S)-Benzamides
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE / HCV / NS5B / POLYMERASE / Acetylation / Apoptosis / ATP-binding / Capsid protein / Envelope protein / Fusion protein / Glycoprotein / Helicase / Host cell membrane / Host cytoplasm / Host endoplasmic reticulum / Host lipid droplet / Host membrane / Host mitochondrion / Host nucleus / Host-virus interaction / Hydrolase / Interferon antiviral system evasion / Lipoprotein / Membrane / Metal-binding / Multifunctional enzyme / Nucleotide-binding / Nucleotidyltransferase / Oncogene / Palmitate / Phosphoprotein / Protease / Ribonucleoprotein / RNA replication / RNA-binding / RNA-directed RNA polymerase / Secreted / Serine protease / SH3-binding / Thiol protease / Transcription / Transcription regulation / Transmembrane / Ubl conjugation / Viral nucleoprotein / Virion / Zinc
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 / molecular adaptor activity / 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. / 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. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-LT6 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.05 Å
AuthorsLesburg, C.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides.
Authors: Cheng, C.C. / Shipps, G.W. / Yang, Z. / Kawahata, N. / Lesburg, C.A. / Duca, J.S. / Bandouveres, J. / Bracken, J.D. / Jiang, C.K. / Agrawal, S. / Ferrari, E. / Huang, H.C.
History
DepositionJan 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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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)129,2164
Polymers128,3832
Non-polymers8332
Water20,1771120
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6082
Polymers64,1921
Non-polymers4161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6082
Polymers64,1921
Non-polymers4161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.700, 107.068, 134.243
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 RNA-directed RNA polymerase / NS5B / p68


Mass: 64191.582 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-LT6 / 2-(2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-oxoethoxy)-N-butyl-6-fluoro-N-methylbenzamide


Mass: 416.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H29FN2O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1120 / 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: 2.48 Å3/Da / Density % sol: 50.45 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.67
Details: 9.0% (w/v) PEG 3350 100 mM Sodium citrate, pH 5.67, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54182 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Aug 1, 2006
RadiationMonochromator: NA / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54182 Å / Relative weight: 1
ReflectionResolution: 2.05→43.37 Å / Num. all: 80870 / Num. obs: 79247 / % possible obs: 98 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 3 / Redundancy: 2.56 % / Biso Wilson estimate: 34.835 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 8.7
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 2.53 % / Rmerge(I) obs: 0.345 / Mean I/σ(I) obs: 2.3 / Num. unique all: 7985 / % possible all: 97.6

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Processing

Software
NameVersionClassification
CrystalCleardata collection
BUSTER-TNT2.1.1refinement
CrystalCleardata reduction
CrystalCleardata scaling
BUSTER-TNT2.1.1phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.05→20 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2413 3952 5 %RANDOM
Rwork0.1841 ---
all0.187 80808 --
obs0.187 79054 97.83 %-
Displacement parametersBiso mean: 37.5 Å2
Baniso -1Baniso -2Baniso -3
1--4.6110728 Å20 Å20 Å2
2---1.26561534 Å20 Å2
3---5.87668814 Å2
Refinement stepCycle: LAST / Resolution: 2.05→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8669 0 60 1120 9849
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.0189672
X-RAY DIFFRACTIONt_angle_deg1.211121142
X-RAY DIFFRACTIONt_dihedral_angle_d17.92117680
X-RAY DIFFRACTIONt_trig_c_planes0.0111832
X-RAY DIFFRACTIONt_gen_planes0.01713775
X-RAY DIFFRACTIONt_it1.625896720
X-RAY DIFFRACTIONt_nbd0.0541815
LS refinement shellResolution: 2.05→2.17 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2618 589 4.71 %
Rwork0.2015 11923 -
all0.2043 12512 -
obs--97.83 %

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