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- PDB-1n1l: CRYSTAL STRUCTURE OF HCV NS3 PROTEASE DOMAIN:NS4A PEPTIDE COMPLEX... -

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Basic information

Entry
Database: PDB / ID: 1n1l
TitleCRYSTAL STRUCTURE OF HCV NS3 PROTEASE DOMAIN:NS4A PEPTIDE COMPLEX WITH COVALENTLY BOUND INHIBITOR (GW472467X)
Components
  • HCV NS3 SERINE PROTEASE
  • NS4A COFACTOR
KeywordsVIRAL PROTEIN / SERINE PROTEASE / NONSTRUCTURAL PROTEINS / COFACTOR PEPTIDE / HELICASE / INHIBITOR
Function / homology
Function and homology information


positive regulation of hexokinase activity / symbiont-mediated perturbation of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / hepacivirin / TBC/RABGAPs / host cell mitochondrial membrane / host cell lipid droplet ...positive regulation of hexokinase activity / symbiont-mediated perturbation of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / hepacivirin / TBC/RABGAPs / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / positive regulation of cytokinesis / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / negative regulation of protein secretion / viral process / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / endoplasmic reticulum-Golgi intermediate compartment membrane / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / SH3 domain binding / virion component / kinase binding / nucleoside-triphosphate phosphatase / channel activity / viral nucleocapsid / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / entry receptor-mediated virion attachment to 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 / ribonucleoprotein complex / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / negative regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
Thrombin, subunit H - #120 / 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 ...Thrombin, subunit H - #120 / 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 / helicase superfamily c-terminal domain / Trypsin-like serine proteases / 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 / Thrombin, subunit H / 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 / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-TRL / : / Non-structural protein 4a/b / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsAndrews, D.M. / Chaignot, H. / Coomber, B.A. / Good, A.C. / Hind, S.L. / Jones, P.S. / Mill, G. / Robinson, J.E. / Skarzynski, T. / Slater, M.J. / Somers, D.O.N.
CitationJournal: Org.Lett. / Year: 2002
Title: Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray Crystal Structure Data in the Optimisation of P3 and P4 Substituents
Authors: Andrews, D.M. / Chaignot, H. / Coomber, B.A. / Good, A.C. / Hind, S.L. / Johnson, M.R. / Jones, P.S. / Mill, G. / Robinson, J.E. / Skarzynski, T. / Slater, M.J. / Somers, D.O.N.
History
DepositionOct 18, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Oct 27, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_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_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HCV NS3 SERINE PROTEASE
B: HCV NS3 SERINE PROTEASE
C: NS4A COFACTOR
D: NS4A COFACTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,4427
Polymers46,8784
Non-polymers5643
Water1,928107
1
A: HCV NS3 SERINE PROTEASE
C: NS4A COFACTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,9384
Polymers23,4392
Non-polymers4992
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3240 Å2
ΔGint-48 kcal/mol
Surface area10140 Å2
MethodPISA
2
B: HCV NS3 SERINE PROTEASE
D: NS4A COFACTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,5043
Polymers23,4392
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-47 kcal/mol
Surface area8450 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7190 Å2
ΔGint-117 kcal/mol
Surface area16360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)225.450, 225.450, 75.890
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

#1: Protein HCV NS3 SERINE PROTEASE


Mass: 21044.975 Da / Num. of mol.: 2 / Fragment: Protease domain / Mutation: A164T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Gene: H STRAIN / Production host: Escherichia coli (E. coli) / References: UniProt: P27958
#2: Protein/peptide NS4A COFACTOR


Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: Residues 21-39 / Source method: obtained synthetically
Details: The peptide was chemically synthesized. The sequence of the protein is naturally found in HEPATITIS C VIRUS type 1B.
References: GenBank: 5748511, UniProt: O39914*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-TRL / {1-[2-(1-FORMYL-PROPYL)-3-METHANESULFONYLAMINO-PYRROLIDINE-1-CARBONYL]-2-METHYL-PROPYL}-CARBAMIC ACID TERT-BUTYL ESTER / GW472467X


Mass: 433.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H35N3O6S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.96 Å3/Da / Density % sol: 68.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Inhibitor soaked into crystal generated according to Kim et al. (1996) Cell, 87, 343-355, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 277.0K
Crystal grow
*PLUS
Details: Kim, J.L., (1996) 8, 344.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Details: MIRRORS
RadiationMonochromator: YALE MIRRORS + Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→40 Å / Num. all: 22723 / Num. obs: 21878 / % possible obs: 96.3 % / Observed criterion σ(I): 1 / Rmerge(I) obs: 0.052 / Net I/σ(I): 16.6
Reflection shellResolution: 2.6→2.69 Å / Rmerge(I) obs: 0.238 / Mean I/σ(I) obs: 4.5 / Num. unique all: 2074 / % possible all: 92
Reflection
*PLUS
Lowest resolution: 40 Å
Reflection shell
*PLUS
% possible obs: 92 %

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Processing

Software
NameVersionClassification
DENZOdata reduction
TRUNCATEdata reduction
REFMACrefinement
CCP4(TRUNCATE)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.931 / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2195 1115 5.1 %RANDOM
Rwork0.18318 ---
all0.18508 20724 --
obs0.18508 20724 100 %-
Solvent computationShrinkage radii: 0.8 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 45.569 Å2
Baniso -1Baniso -2Baniso -3
1--1 Å2-0.5 Å20 Å2
2---1 Å20 Å2
3---1.51 Å2
Refinement stepCycle: LAST / Resolution: 2.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2732 0 31 107 2870
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0212818
X-RAY DIFFRACTIONr_angle_refined_deg1.7411.9773840
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5515366
X-RAY DIFFRACTIONr_chiral_restr0.110.2462
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022071
X-RAY DIFFRACTIONr_nbd_refined0.2370.21165
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1730.2145
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2560.237
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2320.24
X-RAY DIFFRACTIONr_mcbond_it1.63221831
X-RAY DIFFRACTIONr_mcangle_it3.30542973
X-RAY DIFFRACTIONr_scbond_it5.4926987
X-RAY DIFFRACTIONr_scangle_it8.5839867
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.36 72
Rwork0.266 1441
Refinement
*PLUS
Highest resolution: 2.6 Å / Lowest resolution: 20 Å / Rfactor Rfree: 0.22 / Rfactor Rwork: 0.183
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_d0.016
X-RAY DIFFRACTIONr_angle_d
X-RAY DIFFRACTIONr_angle_deg1.741

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