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- PDB-2xcf: Crystal structure of HCV NS3 protease with a boronate inhibitor -

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Basic information

Entry
Database: PDB / ID: 2xcf
TitleCrystal structure of HCV NS3 protease with a boronate inhibitor
Components
  • NS3 PROTEASE
  • NS4A
KeywordsHYDROLASE / PROTEASE / BORONATE INHIBITOR / VIRAL REPRODUCTION
Function / homology
Function and homology information


transformation of host cell by virus / viral process / serine-type peptidase activity / virion component / ATP binding / metal ion binding
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan ...Thrombin, subunit H - #120 / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-BBQ / NS3 protease / Polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.48 Å
AuthorsLi, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Li, Q. / Zhou, Y. / Plattner, J.J. / Baker, S.J. / Qian, X. / Fan, D. ...Li, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Li, Q. / Zhou, Y. / Plattner, J.J. / Baker, S.J. / Qian, X. / Fan, D. / Liao, L. / Ni, Z.-J. / White, G.V. / Mordaunt, J.E. / Lazarides, L.X. / Slater, M.J. / Jarvest, R.L. / Thommes, P. / Ellis, M. / Edge, C.M. / Hubbard, J.A. / Nassau, P. / McDowell, B. / Skarzynski, T.J. / Rowland, P. / Somers, D.O. / Kazmierski, W.M. / Grimes, R.M. / Wright, L.L. / Smith, G.K. / Zou, W. / Wright, J. / Pennicott, L.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Synthesis and Evaluation of Novel Alpha-Amino Cyclic Boronates as Inhibitors of Hcv Ns3 Protease.
Authors: Li, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Li, Q. / Zhou, Y. / Plattner, J.J. / Baker, S.J. / Qian, X. / Fan, D. / Liao, L. / Ni, Z.-J. / White, G.V. / Mordaunt, J.E. / Lazarides, L.X. / ...Authors: Li, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Li, Q. / Zhou, Y. / Plattner, J.J. / Baker, S.J. / Qian, X. / Fan, D. / Liao, L. / Ni, Z.-J. / White, G.V. / Mordaunt, J.E. / Lazarides, L.X. / Slater, M.J. / Jarvest, R.L. / Edge, C.M. / Hubbard, J.A. / Nassau, P. / Mcdowell, B. / Skarzynski, T.J. / Thommes, P. / Ellis, M. / Rowland, P. / Somers, D.O. / Kazmierski, W.M. / Grimes, R.M. / Wright, L.L. / Smith, G.K. / Zou, W. / Wright, J. / Pennicott, L.E.
History
DepositionApr 22, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)47,6059
Polymers46,7864
Non-polymers8195
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6890 Å2
ΔGint-136.1 kcal/mol
Surface area16290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)225.889, 225.889, 75.196
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein NS3 PROTEASE


Mass: 20998.949 Da / Num. of mol.: 2 / Fragment: PROTEASE DOMAIN, RESIDUES 1-180 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS / Strain: H STRAIN / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: C1KHN2
#2: Protein/peptide NS4A /


Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: RESIDUES 21-39 / Source method: obtained synthetically / Source: (synth.) HEPATITIS C VIRUS / References: UniProt: C9WU77

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Non-polymers , 4 types, 120 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-BBQ / CYCLOPENTYL N-[(2S)-1-[(2S,4R)-2-[[(4R)-8-HYDROXY-1,6,10-TRIOXA-5$L^{4}-BORASPIRO[4.5]DECAN-4-YL]CARBAMOYL]-4-ISOQUINOLIN-1-YLOXY-PYRROLIDIN-1-YL]-3,3-DIMETHYL-1-OXO-BUTAN-2-YL]CARBAMATE


Mass: 639.524 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H44BN4O9
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 115 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, SER 139 TO ALA ENGINEERED RESIDUE IN CHAIN B, SER 139 TO ALA
Nonpolymer detailsCYCLIC BORONATE - GLYCEROL ADDUCT (BBQ): THIS IS INTERPRETED AS A SPIROCYCLIC GLYCEROL ADDUCT OF ...CYCLIC BORONATE - GLYCEROL ADDUCT (BBQ): THIS IS INTERPRETED AS A SPIROCYCLIC GLYCEROL ADDUCT OF THE CYCLIC BORONATE INHIBITOR

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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: 3.9 Å3/Da / Density % sol: 68.8 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: ADSC CCD / Detector: CCD / Date: May 14, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.47→70 Å / Num. obs: 26049 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 11.4
Reflection shellResolution: 2.47→2.6 Å / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 3.5 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.48→70.19 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.935 / SU B: 6.238 / SU ML: 0.141 / Cross valid method: THROUGHOUT / ESU R: 0.229 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22608 1326 5.1 %RANDOM
Rwork0.19363 ---
obs0.19529 24721 100 %-
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: 45.626 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å2-0.44 Å20 Å2
2---0.88 Å20 Å2
3---1.33 Å2
Refinement stepCycle: LAST / Resolution: 2.48→70.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2726 0 50 115 2891
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222848
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4791.9943877
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2345368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.40521.59694
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.87915442
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4851527
X-RAY DIFFRACTIONr_chiral_restr0.0860.2468
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0222069
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.49921839
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.93742973
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.37641009
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.3376903
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.478→2.542 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 102 -
Rwork0.292 1809 -
obs--100 %

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