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- PDB-3frz: Crystal Structure of HCV NS5B RNA polymerase in complex with PF868554 -

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Basic information

Entry
Database: PDB / ID: 3frz
TitleCrystal Structure of HCV NS5B RNA polymerase in complex with PF868554
ComponentsRNA-directed RNA polymerase
KeywordsTRANSFERASE / viral polymerase / Acetylation / Apoptosis / ATP-binding / Capsid protein / Cell membrane / Cytoplasm / Endoplasmic reticulum / Envelope protein / Fusion protein / Glycoprotein / Helicase / Host-virus interaction / Hydrolase / Interferon antiviral system evasion / Lipid droplet / Lipoprotein / Membrane / Metal-binding / Mitochondrion / Multifunctional enzyme / Nucleotide-binding / Nucleotidyltransferase / Nucleus / 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 / 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 / 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 / Reverse transcriptase/Diguanylate cyclase domain / 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 / Alpha-Beta Plaits / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-AG0 / Chem-AG6 / BETA-MERCAPTOETHANOL / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.86 Å
AuthorsParge, H.E.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and ...Title: Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor.
Authors: Li, H. / Tatlock, J. / Linton, A. / Gonzalez, J. / Jewell, T. / Patel, L. / Ludlum, S. / Drowns, M. / Rahavendran, S.V. / Skor, H. / Hunter, R. / Shi, S.T. / Herlihy, K.J. / Parge, H. / ...Authors: Li, H. / Tatlock, J. / Linton, A. / Gonzalez, J. / Jewell, T. / Patel, L. / Ludlum, S. / Drowns, M. / Rahavendran, S.V. / Skor, H. / Hunter, R. / Shi, S.T. / Herlihy, K.J. / Parge, H. / Hickey, M. / Yu, X. / Chau, F. / Nonomiya, J. / Lewis, C.
History
DepositionJan 8, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3744
Polymers64,1781
Non-polymers1,1953
Water11,890660
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.200, 83.200, 180.263
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein RNA-directed RNA polymerase / NS5B / p68


Mass: 64178.418 Da / Num. of mol.: 1 / Fragment: sequence database residues 2420-2989 / Mutation: K114R, L47Q, F101Y, V59D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Strain: 1b / Gene: NS5B / Production host: Escherichia coli (E. coli) / Strain (production host): DH5alpha / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-AG0 / (6R)-6-cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one


Mass: 503.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H37N5O3 / Comment: inhibitor*YM
#3: Chemical ChemComp-AG6 / N-[(benzyloxy)carbonyl]-L-alpha-glutamyl-N-[(1S)-4-oxo-4-phenyl-1-propylbut-2-en-1-yl]-L-phenylalaninamide


Mass: 613.700 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H39N3O7
#4: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 660 / 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

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
12.4349.39
2
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: Stock crystals generated from 2uL Protein:AG9322(1:5)+ 2uL precipitant equilibrated against reservoir 18.0% PEG 3K, 0.1M Citrate pH 5.5, 14% Glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 101 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Aug 6, 2004 / Details: OSMIC CONFOCAL OPTICS
RadiationMonochromator: OSMIC CONFOCAL OPTICS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.86→10 Å / Num. all: 52311 / Num. obs: 52311 / % possible obs: 97.4 % / Redundancy: 11.98 % / Rsym value: 0.033
Reflection shellResolution: 1.86→1.93 Å / Redundancy: 11.9 % / Mean I/σ(I) obs: 13.4 / Num. unique all: 5021 / Rsym value: 0.205 / % possible all: 95.3

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
ARP/wARPmodel building
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.86→10 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.946 / SU B: 2.682 / SU ML: 0.082 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / ESU R: 0.139 / ESU R Free: 0.135 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 2662 5.1 %RANDOM
Rwork0.17487 ---
obs0.17726 49603 97.47 %-
all-52311 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 26.046 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2---0.11 Å20 Å2
3---0.21 Å2
Refinement stepCycle: LAST / Resolution: 1.86→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4325 0 69 660 5054
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0214503
X-RAY DIFFRACTIONr_bond_other_d0.0020.024090
X-RAY DIFFRACTIONr_angle_refined_deg1.4821.9696120
X-RAY DIFFRACTIONr_angle_other_deg0.85739481
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5165561
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0950.2687
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025000
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02923
X-RAY DIFFRACTIONr_nbd_refined0.2120.2896
X-RAY DIFFRACTIONr_nbd_other0.250.24733
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0850.22637
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2413
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1580.26
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2350.248
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1970.222
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9131.52805
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.66124524
X-RAY DIFFRACTIONr_scbond_it2.61731698
X-RAY DIFFRACTIONr_scangle_it4.0354.51596
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.86→1.906 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.289 190
Rwork0.205 3428

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