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- PDB-2dxs: Crystal structure of HCV NS5B RNA polymerase complexed with a tet... -

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Basic information

Entry
Database: PDB / ID: 2dxs
TitleCrystal structure of HCV NS5B RNA polymerase complexed with a tetracyclic inhibitor
ComponentsGenome polyprotein
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / HCV / NS5B / RNA polymerase / 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 / 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-JTP / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAdachi, T. / Tsuruha, J. / Doi, S. / Murase, K. / Ikegashira, K. / Watanabe, S. / Uehara, K. / Orita, T. / Nomura, A. / Kamada, M.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors
Authors: Ikegashira, K. / Oka, T. / Hirashima, S. / Noji, S. / Yamanaka, H. / Hara, Y. / Adachi, T. / Tsuruha, J. / Doi, S. / Hase, Y. / Noguchi, T. / Ando, I. / Ogura, N. / Ikeda, S. / Hashimoto, H.
History
DepositionAug 30, 2006Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 26, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 25, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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: Genome polyprotein
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,6084
Polymers122,7152
Non-polymers8932
Water10,521584
1
A: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8042
Polymers61,3571
Non-polymers4471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8042
Polymers61,3571
Non-polymers4471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.454, 67.231, 97.853
Angle α, β, γ (deg.)90.00, 93.78, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Genome polyprotein / NS5B / p68


Mass: 61357.328 Da / Num. of mol.: 2 / Fragment: RNA-directed RNA polymerase, RESIDUES 2419-2962
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Strain: BK / Gene: 1B / Plasmid: pET17b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21 (DE3) / References: UniProt: P26663, RNA-directed RNA polymerase
#2: Chemical ChemComp-JTP / N-[(13-CYCLOHEXYL-6,7-DIHYDROINDOLO[1,2-D][1,4]BENZOXAZEPIN-10-YL)CARBONYL]-2-METHYL-L-ALANINE / 2-[(12-CYCLOHEXYL-6,7-DIHYDRO-5-OXA-7A-AZA-DIBENZO[A,E]AZULENE-9-CARBONYL)-AMINO]-2-METHYL-PROPIONIC ACID


Mass: 446.538 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H30N2O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 584 / 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: 2.58 Å3/Da / Density % sol: 52.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1M Citrate, 8% PEG 8000, 5% 2-propanol, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 277.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 9, 2004
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 63257 / % possible obs: 99.3 % / Redundancy: 3.6 % / Biso Wilson estimate: 17.6 Å2 / Rmerge(I) obs: 0.122 / Net I/σ(I): 10.4
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 3.3 / % possible all: 98.3

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Processing

Software
NameVersionClassification
CNX2005refinement
MOSFLMdata reduction
CCP4(SCALA)data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1QUV

1quv


Resolution: 2.2→29.99 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 1821441.43 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.259 3217 5.1 %RANDOM
Rwork0.217 ---
obs0.219 63249 99 %-
all-63249 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 53.4971 Å2 / ksol: 0.394713 e/Å3
Displacement parametersBiso mean: 30.4 Å2
Baniso -1Baniso -2Baniso -3
1--12.45 Å20 Å2-0.03 Å2
2---4.39 Å20 Å2
3---16.83 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.26 Å
Refinement stepCycle: LAST / Resolution: 2.2→29.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8040 0 66 584 8690
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.338
X-RAY DIFFRACTIONc_angle_deg1.7
X-RAY DIFFRACTIONc_dihedral_angle_d19.3
X-RAY DIFFRACTIONc_improper_angle_d1.03
X-RAY DIFFRACTIONc_mcbond_it1.361.5
X-RAY DIFFRACTIONc_mcangle_it2.152
X-RAY DIFFRACTIONc_scbond_it2.032
X-RAY DIFFRACTIONc_scangle_it2.782.5
LS refinement shellResolution: 2.2→2.34 Å / Rfactor Rfree error: 0.014 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.308 517 5 %
Rwork0.266 9840 -
obs--98.2 %

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