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

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Basic information

Entry
Database: PDB / ID: 3uph
TitleSynthesis of novel 4,5-dihydrofurano indoles and their evaluation as HCV NS5B polymerase inhibitors
ComponentsRNA-directed 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 / 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 / channel activity / monoatomic ion transmembrane transport / 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 / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / ribonucleoprotein complex / 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 / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / 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 NS2, C-terminal domain / 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, 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 NS2, C-terminal domain / Hepatitis C virus core protein, chain A superfamily / : / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / 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 zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepatitis C virus, Non-structural protein NS2 / : / NS3 RNA helicase, C-terminal helical domain / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus non-structural 5a protein membrane anchor / 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 / Hepacivirus/Pegivirus NS3 protease domain profile. / Hepatitis C virus NS3 protease / 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-0C1 / PHOSPHATE ION / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / 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
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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

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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)129,4775
Polymers128,3832
Non-polymers1,0943
Water18,2311012
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7863
Polymers64,1921
Non-polymers5942
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6912
Polymers64,1921
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.970, 106.328, 134.297
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


Mass: 64191.582 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


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-0C1 / 6-(2,5-difluorobenzyl)-N-(methylsulfonyl)-8-(2-oxo-1,2-dihydropyridin-3-yl)-3,6-dihydro-2H-furo[2,3-e]indole-7-carboxamide


Mass: 499.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19F2N3O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1012 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.5 Å3/Da / Density % sol: 50.83 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5.9
Details: 11.6% w/v PEG3350, 0.1 M sodium citrate, pH 5.9, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 30, 2006
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. all: 89492 / Num. obs: 76031 / % possible obs: 86.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4.2 % / Biso Wilson estimate: 27.03 Å2 / Rmerge(I) obs: 0.076
Reflection shellResolution: 2→2.07 Å / % possible all: 64.7

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Processing

Software
NameVersionClassification
JDirectordata collection
BUSTER2.9.4refinement
DENZOdata reduction
SCALEPACKdata scaling
BUSTER2.9.4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→19.89 Å / Cor.coef. Fo:Fc: 0.9384 / Cor.coef. Fo:Fc free: 0.9128 / SU R Cruickshank DPI: 0.202 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.22 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.174 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2299 3755 4.97 %RANDOM
Rwork0.1848 ---
all0.187 87463 --
obs0.187 75551 86.38 %-
Displacement parametersBiso mean: 31.24 Å2
Baniso -1Baniso -2Baniso -3
1--5.5067 Å20 Å20 Å2
2---1.7367 Å20 Å2
3---7.2434 Å2
Refine analyzeLuzzati coordinate error obs: 0.218 Å
Refinement stepCycle: LAST / Resolution: 2→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8735 0 75 1012 9822
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3102SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes196HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1433HARMONIC5
X-RAY DIFFRACTIONt_it9033HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1198SEMIHARMONIC5
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_contact11463SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9033HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12274HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion15.87
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2239 191 4.87 %
Rwork0.2012 3727 -
all0.2024 3918 -
obs--86.38 %

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