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- PDB-5pzp: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA... -

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Basic information

Entry
Database: PDB / ID: 5pzp
TitleCRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 4-FLUORO-2-(4-FLUOROPHENYL)-N-METHYL-5-(2-METHYL-5-{[1-(PYRIMIDIN-2-YL)CYCLOPROPYL]CARBAMOYL}PHENYL)-1-BENZOFURAN-3-CARBOXAMIDE (BMS-929075)
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE / NS5B / POLYMERASE / HCV / FINGERS / PALM / THUMB
Function / homology
Function and homology information


positive stranded viral RNA replication / 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 / viral genome replication ...positive stranded viral RNA replication / 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 / viral genome replication / 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 / 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 / protein-containing complex / proteolysis / RNA binding / zinc ion binding / ATP binding / identical protein 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, 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 core protein, chain A superfamily / : / 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 / NS3 RNA helicase, C-terminal helical domain / 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-23E / Chem-8XJ / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus genotype 1b
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.95 Å
AuthorsSheriff, S.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.
Authors: Yeung, K.S. / Beno, B.R. / Parcella, K. / Bender, J.A. / Grant-Young, K.A. / Nickel, A. / Gunaga, P. / Anjanappa, P. / Bora, R.O. / Selvakumar, K. / Rigat, K. / Wang, Y.K. / Liu, M. / Lemm, ...Authors: Yeung, K.S. / Beno, B.R. / Parcella, K. / Bender, J.A. / Grant-Young, K.A. / Nickel, A. / Gunaga, P. / Anjanappa, P. / Bora, R.O. / Selvakumar, K. / Rigat, K. / Wang, Y.K. / Liu, M. / Lemm, J. / Mosure, K. / Sheriff, S. / Wan, C. / Witmer, M. / Kish, K. / Hanumegowda, U. / Zhuo, X. / Shu, Y.Z. / Parker, D. / Haskell, R. / Ng, A. / Gao, Q. / Colston, E. / Raybon, J. / Grasela, D.M. / Santone, K. / Gao, M. / Meanwell, N.A. / Sinz, M. / Soars, M.G. / Knipe, J.O. / Roberts, S.B. / Kadow, J.F.
History
DepositionFeb 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)131,39818
Polymers127,9232
Non-polymers3,47516
Water18010
1
A: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,79110
Polymers63,9621
Non-polymers1,8309
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: RNA-directed RNA polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,6078
Polymers63,9621
Non-polymers1,6467
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.200, 90.700, 234.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein RNA-directed RNA polymerase


Mass: 63961.516 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus genotype 1b (isolate Con1)
Strain: isolate Con1 / Plasmid: PET21b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9WMX2, RNA-directed RNA polymerase

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Non-polymers , 5 types, 26 molecules

#2: Chemical ChemComp-23E / (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid


Mass: 630.732 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H38N4O5
#3: Chemical ChemComp-8XJ / 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-{[1-(pyrimidin-2-yl)cyclopropyl]carbamoyl}phenyl)-1-benzofuran-3-carboxamide


Mass: 538.544 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H24F2N4O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.71 Å3/Da / Density % sol: 54.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6 / Details: 100 mM sodium citrate, pH 5.6, 1.75 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9793 / Wavelength: 0.9793 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Sep 26, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. obs: 30164 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 74.45 Å2 / Rsym value: 0.088 / Net I/σ(I): 14.6
Reflection shellResolution: 2.95→3.06 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.7 / Rsym value: 0.478 / Rejects: 0 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data collection
HKL-2000data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3Q0Z

3q0z


Resolution: 2.95→43.86 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.883 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.376
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1057 3.51 %RANDOM
Rwork0.199 ---
obs0.201 30104 99.7 %-
Displacement parametersBiso max: 187.23 Å2 / Biso mean: 66.79 Å2 / Biso min: 13.59 Å2
Baniso -1Baniso -2Baniso -3
1--15.0753 Å20 Å20 Å2
2---3.658 Å20 Å2
3---18.7333 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.95→43.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8285 0 238 10 8533
Biso mean--61.05 38.77 -
Num. residues----1080
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2963SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes156HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1483HARMONIC5
X-RAY DIFFRACTIONt_it8834HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1139SEMIHARMONIC5
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_contact10485SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8834HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12129HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion17.53
LS refinement shellResolution: 2.95→3.05 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.306 102 3.57 %
Rwork0.225 2753 -
all0.228 2855 -
obs--98.78 %

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