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- PDB-3upi: Synthesis of novel 4,5-dihydrofurano indoles and their evaluation... -

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Basic information

Entry
Database: PDB / ID: 3upi
TitleSynthesis of novel 4,5-dihydrofurano indoles and their evaluation as HCV NS5B polymerase inhibitors
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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 / : ...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 / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / molecular adaptor activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / ribonucleoprotein complex / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / host cell plasma membrane / 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 non-structural protein NS4b ...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 / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-0C2 / PHOSPHATE ION / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsVelazquez, F. / Venkataraman, S. / Lesburg, C.A. / Duca, J.S. / Rosenblum, S.B. / Kozlowski, J.A. / Njoroge, F.G.
CitationJournal: Org.Lett. / Year: 2012
Title: Synthesis of New 4,5-Dihydrofuranoindoles and Their Evaluation as HCV NS5B Polymerase Inhibitors.
Authors: Velazquez, F. / Venkatraman, S. / Lesburg, C.A. / Duca, J. / Rosenblum, S.B. / Kozlowski, J.A. / Njoroge, F.G.
History
DepositionNov 18, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)131,7625
Polymers130,6402
Non-polymers1,1223
Water16,826934
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9283
Polymers65,3201
Non-polymers6082
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8332
Polymers65,3201
Non-polymers5141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.816, 106.538, 134.274
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 / RNA-dependent RNA polymerase / NS5B


Mass: 65319.805 Da / Num. of mol.: 2 / Fragment: UNP residues 2420-2989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: HC-J4 / Production host: Escherichia coli (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-0C2 / (3S)-6-(2,5-difluorobenzyl)-3-methyl-N-(methylsulfonyl)-8-(2-oxo-1,2-dihydropyridin-3-yl)-3,6-dihydro-2H-furo[2,3-e]indole-7-carboxamide


Mass: 513.513 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H21F2N3O5S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 934 / 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: 2.46 Å3/Da / Density % sol: 49.97 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.97
Details: 12.2% w/v PEG3350, 0.1 M sodium citrate, pH 5.97, 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: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 4, 2007
RadiationMonochromator: Varimax HR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. all: 87612 / Num. obs: 87525 / % possible obs: 99.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 37.91 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 8.9
Reflection shellResolution: 2→2.07 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.439 / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
StructureStudiodata collection
BUSTER2.9.4refinement
d*TREKdata reduction
d*TREKdata scaling
BUSTER2.9.4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.9449 / Cor.coef. Fo:Fc free: 0.9228 / SU R Cruickshank DPI: 0.171 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.182 / SU Rfree Blow DPI: 0.162 / SU Rfree Cruickshank DPI: 0.158
RfactorNum. reflection% reflectionSelection details
Rfree0.2355 4345 4.98 %RANDOM
Rwork0.1893 ---
all0.1916 87463 --
obs0.1916 87262 99.77 %-
Displacement parametersBiso mean: 41.36 Å2
Baniso -1Baniso -2Baniso -3
1--8.0814 Å20 Å20 Å2
2---0.6619 Å20 Å2
3---8.7433 Å2
Refine analyzeLuzzati coordinate error obs: 0.224 Å
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8735 0 77 934 9746
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3108SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes222HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1569HARMONIC5
X-RAY DIFFRACTIONt_it9129HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1206SEMIHARMONIC5
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_contact11317SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9129HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12422HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion15.52
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2612 307 4.81 %
Rwork0.2193 6076 -
all0.2214 6383 -
obs--99.77 %

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