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- PDB-4gmc: Crystal structure of HCV NS5B polymerase in complex with a thumb ... -

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Basic information

Entry
Database: PDB / ID: 4gmc
TitleCrystal structure of HCV NS5B polymerase in complex with a thumb inhibitor
ComponentsNS5B 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 / protein complex oligomerization / monoatomic ion channel activity / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / ribonucleoprotein complex / induction by virus of host autophagy / 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 / host cell plasma membrane / structural molecule activity / virion membrane / 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 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. / 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-1BI / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsCoulombe, R.
CitationJournal: Can.J.Chem. / Year: 2013
Title: Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase - Acylsulfonamides and acylsulfamides as carboxylic acid replacements
Authors: Beaulieu, P.L. / Coulombe, R. / Gillard, J. / Brochu, C. / Duan, J. / Garneau, M. / Jolicoeur, E. / Kuhn, P. / Poupart, M.A. / Rancourt, J. / Stammers, T.A. / Thavonekham, B. / Kukolj, G.
History
DepositionAug 15, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 20, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 13, 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: NS5B polymerase
B: NS5B polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,5317
Polymers128,5712
Non-polymers9605
Water1,13563
1
A: NS5B polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4783
Polymers64,2861
Non-polymers1922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: NS5B polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0534
Polymers64,2861
Non-polymers7683
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)104.240, 106.260, 133.330
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 NS5B polymerase / RNA-directed RNA polymerase


Mass: 64285.637 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 / Plasmid: pET29B / Production host: Escherichia coli (E. coli) / Strain (production host): JM109(DE3) / References: UniProt: O92972, RNA-directed RNA polymerase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-1BI / 3-cyclohexyl-2-(furan-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-N-(phenylsulfonyl)-1H-indole-6-carboxamide


Mass: 575.675 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H33N3O6S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.87 Å3/Da / Density % sol: 57.17 %
Crystal growTemperature: 284 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: 100 mM MES, 21% PEG5000 MME, 400 mM ammonium sulfate, 10% glycerol, pH 5.4, VAPOR DIFFUSION, HANGING DROP, temperature 284K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 1, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 41572 / Num. obs: 41572 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4.17 % / Rmerge(I) obs: 0.092 / Net I/σ(I): 13.94
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2.5 / % possible all: 100

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Processing

Software
NameClassification
HKL-2000data collection
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3MWV

3mwv


Resolution: 2.7→50 Å / Occupancy max: 1 / Occupancy min: 1 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2566 4127 10 %RANDOM
Rwork0.2186 37200 --
all-41572 --
obs-41327 100 %-
Displacement parametersBiso max: 119.23 Å2 / Biso mean: 51.0501 Å2 / Biso min: 16.51 Å2
Baniso -1Baniso -2Baniso -3
1--10.398 Å20 Å20 Å2
2--2.464 Å20 Å2
3---7.934 Å2
Refinement stepCycle: LAST / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8568 0 61 63 8692
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.426
X-RAY DIFFRACTIONc_mcbond_it1.2511.5
X-RAY DIFFRACTIONc_scbond_it1.8822
X-RAY DIFFRACTIONc_mcangle_it2.1432
X-RAY DIFFRACTIONc_scangle_it2.8382.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:dna-rna_rep.paramMSI_CNX_TOPPAR:dna-rna.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5bi.parbi.top

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