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- PDB-3u4r: Novel HCV NS5B polymerase Inhibitors: Discovery of Indole C2 Acyl... -

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Basic information

Entry
Database: PDB / ID: 3u4r
TitleNovel HCV NS5B polymerase Inhibitors: Discovery of Indole C2 Acyl sulfonamides
ComponentsRNA-directed RNA polymeraseRNA-dependent RNA polymerase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / nucleotidyl transfer / 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 / ribonucleoprotein complex / RNA-directed RNA polymerase / 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 / 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 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 / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-08F / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsAnilkumar, G.N. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.-Y. / Pu, H. / Wang, L. / Bennett, F. / Chen, K.X. ...Anilkumar, G.N. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.-Y. / Pu, H. / Wang, L. / Bennett, F. / Chen, K.X. / Lesburg, C.A. / Duca, J.S. / Gavalas, S. / Huang, Y. / Pinto, P. / Sannagrahi, M. / Velazquez, F. / Venkataraman, S. / Vilbubhan, B. / Agrawal, S. / Ferrari, E. / Jiang, C.-K. / Huang, H.-C. / Shih, N.-Y. / Njoroge, F.G. / Kozlowski, J.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: II. Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 acyl sulfonamides.
Authors: Anilkumar, G.N. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.Y. / Pu, H. / Wang, L. / Bennett, F. / Chen, K.X. / Lesburg, C.A. / Duca, J. / Gavalas, S. / Huang, Y. / ...Authors: Anilkumar, G.N. / Selyutin, O. / Rosenblum, S.B. / Zeng, Q. / Jiang, Y. / Chan, T.Y. / Pu, H. / Wang, L. / Bennett, F. / Chen, K.X. / Lesburg, C.A. / Duca, J. / Gavalas, S. / Huang, Y. / Pinto, P. / Sannigrahi, M. / Velazquez, F. / Venkatraman, S. / Vibulbhan, B. / Agrawal, S. / Ferrari, E. / Jiang, C.K. / Huang, H.C. / Shih, N.Y. / George Njoroge, F. / Kozlowski, J.A.
History
DepositionOct 10, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2011Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2012Group: Database references
Revision 1.2Feb 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

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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)130,1904
Polymers128,9362
Non-polymers1,2542
Water23,8161322
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0952
Polymers64,4681
Non-polymers6271
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0952
Polymers64,4681
Non-polymers6271
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.922, 106.681, 134.317
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 RNA-dependent RNA polymerase / p68


Mass: 64467.902 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 / Gene: NS5B / Production host: Escherichia coli (E. coli) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical ChemComp-08F / 1-[(2-aminopyridin-4-yl)methyl]-5-chloro-N-({3-[(methylsulfonyl)amino]phenyl}sulfonyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide


Mass: 627.091 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H23ClN6O6S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1322 / 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: 2.5 Å3/Da / Density % sol: 50.77 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 15.0% w/v Miralax (PEG3350), 0.1 M citrate, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 9, 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→30.41 Å / Num. all: 87454 / Num. obs: 87454 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Biso Wilson estimate: 37.59 Å2
Reflection shellResolution: 2→2.07 Å / % possible all: 96.2

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Processing

Software
NameVersionClassification
StructureStudiodata collection
autoBUSTERmodel building
BUSTER2.11.1refinement
CrystalCleardata reduction
CrystalCleardata scaling
autoBUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.9483 / Cor.coef. Fo:Fc free: 0.9294 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.198 / SU Rfree Blow DPI: 0.169 / SU Rfree Cruickshank DPI: 0.161 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2369 4337 4.98 %RANDOM
Rwork0.1921 ---
all0.1944 87093 --
obs0.1944 87093 99.31 %-
Displacement parametersBiso mean: 41.2 Å2
Baniso -1Baniso -2Baniso -3
1--7.9748 Å20 Å20 Å2
2--1.5789 Å20 Å2
3---6.396 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8694 0 84 1322 10100
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3072SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes196HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1440HARMONIC5
X-RAY DIFFRACTIONt_it8974HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1186SEMIHARMONIC5
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_contact11960SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8974HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12190HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion17.37
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2503 313 4.88 %
Rwork0.214 6100 -
all0.2159 6413 -
obs--99.31 %

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