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- PDB-2xni: Protein-ligand complex of a novel macrocyclic HCV NS3 protease in... -

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Basic information

Entry
Database: PDB / ID: 2xni
TitleProtein-ligand complex of a novel macrocyclic HCV NS3 protease inhibitor derived from amino cyclic boronates
Components
  • NS3 PROTEASE
  • NS4A COFACTOR
KeywordsHYDROLASE/HYDROLASE REGULATOR / HYDROLASE-HYDROLASE REGULATOR COMPLEX / SERINE PROTEASE
Function / homology
Function and homology information


positive regulation of hexokinase activity / modulation by virus 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 / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet ...positive regulation of hexokinase activity / modulation by virus 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 / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / positive regulation of cytokinesis / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / negative regulation of protein secretion / 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 / endoplasmic reticulum-Golgi intermediate compartment membrane / viral process / serine-type peptidase activity / virion component / SH3 domain binding / kinase binding / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / entry receptor-mediated virion attachment to host cell / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / ribonucleoprotein complex / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / 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 / 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 ...Thrombin, subunit H - #120 / 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. / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal 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 / Trypsin-like serine proteases / 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-TR8 / NS3 protease / Polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHEPATITIS C VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 3.3 Å
AuthorsLi, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Zhou, Y. / Li, Q. / Plattner, J.J. / Baker, S.J. / Zhang, S. / Kazmierski, W.M. ...Li, X. / Zhang, Y.-K. / Liu, Y. / Ding, C.Z. / Zhou, Y. / Li, Q. / Plattner, J.J. / Baker, S.J. / Zhang, S. / Kazmierski, W.M. / Wright, L.L. / Smith, G.K. / Grimes, R.M. / Crosby, R.M. / Creech, K.L. / Carballo, L.H. / Slater, M.J. / Jarvest, R.L. / Thommes, P. / Hubbard, J.A. / Convery, M.A. / Nassau, P.M. / McDowell, W. / Skarzynski, T.J. / Qian, X. / Fan, D. / Liao, L. / Ni, Z.-J. / Pennicott, L.E. / Zou, W. / Wright, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Novel Macrocyclic Hcv Ns3 Protease Inhibitors Derived from Alpha-Amino Cyclic Boronates.
Authors: Li, X. / Zhang, Y. / Liu, Y. / Ding, C.Z. / Zhou, Y. / Li, Q. / Plattner, J.J. / Baker, S.J. / Zhang, S. / Kazmierski, W.M. / Wright, L.L. / Smith, G.K. / Grimes, R.M. / Crosby, R.M. / ...Authors: Li, X. / Zhang, Y. / Liu, Y. / Ding, C.Z. / Zhou, Y. / Li, Q. / Plattner, J.J. / Baker, S.J. / Zhang, S. / Kazmierski, W.M. / Wright, L.L. / Smith, G.K. / Grimes, R.M. / Crosby, R.M. / Creech, K.L. / Carballo, L.H. / Slater, M.J. / Jarvest, R.L. / Thommes, P. / Hubbard, J.A. / Convery, M.A. / Nassau, P.M. / Mcdowell, W. / Skarzynski, T.J. / Qian, X. / Fan, D. / Liao, L. / Ni, Z.-J. / Pennicott, L.E. / Zou, W. / Wright, J.
History
DepositionAug 2, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 17, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2012Group: Database references
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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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 COFACTOR
D: NS4A COFACTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6619
Polymers46,8184
Non-polymers8435
Water1,11762
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6860 Å2
ΔGint-139.3 kcal/mol
Surface area16910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)233.289, 233.289, 78.067
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: 21014.949 Da / Num. of mol.: 2 / Fragment: PROTEASE DOMAIN, RESIDUES 1-180
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HEPATITIS C VIRUS / Strain: H / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: C1KHZ7, UniProt: P27958*PLUS
#2: Protein/peptide NS4A COFACTOR


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, 67 molecules

#3: Chemical ChemComp-TR8 / (1-{[(10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19,23,23a-tetradecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosin-7(3H)-yl)carbonyl]amino}-3-hydroxypropyl)(trihydroxy)borate(1-)


Mass: 663.587 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H52BN4O10
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer details[(1R)-1-({[(1R,21S,24S)-21-(1,1-DIMETHYLETHYL)-16, 16-DIMETHYL-3,19,22-TRIOXO-2,18-DIOXA-4,20, 23- ...[(1R)-1-({[(1R,21S,24S)-21-(1,1-DIMETHYLETHYL)-16, 16-DIMETHYL-3,19,22-TRIOXO-2,18-DIOXA-4,20, 23-TRIAZATETRACYCLO[21.2.1.1.0]HEPTACOSA-6,8, 10-TRIEN-24-YL]CARBONYL}AMINO)-3-HYDROXYPROPYL]BORONIC ACID (TR8): 5 MEMBERED B-CONTAINING RING HAS RING OPENED AND B IS COVALENTLY ATTACHED TO S139

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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: 4.37 Å3/Da / Density % sol: 71.83 % / Description: NONE
Crystal growpH: 6.5 / Details: pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 17, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 3.3→117 Å / Num. obs: 12273 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 99.6 Å2 / Rmerge(I) obs: 0.22 / Net I/σ(I): 2.8
Reflection shellResolution: 3.3→3.48 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 1.1 / % possible all: 99.8

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Processing

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

Resolution: 3.3→117.04 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.875 / SU B: 20.837 / SU ML: 0.333 / Cross valid method: THROUGHOUT / ESU R: 2.073 / ESU R Free: 0.413 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. BINDING MODE OF LIGAND SUPPORTED BY UNPUBLISHED DATA.
RfactorNum. reflection% reflectionSelection details
Rfree0.24922 588 4.8 %RANDOM
Rwork0.20211 ---
obs0.20444 11685 99.65 %-
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: 66.855 Å2
Baniso -1Baniso -2Baniso -3
1--1.02 Å2-0.51 Å20 Å2
2---1.02 Å20 Å2
3---1.53 Å2
Refinement stepCycle: LAST / Resolution: 3.3→117.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2732 0 50 62 2844
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222844
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.271.9943868
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5155367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.8521.7293
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.13115441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7251526
X-RAY DIFFRACTIONr_chiral_restr0.0770.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0222089
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_it0.89421840
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.77242974
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.80441004
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.096894
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: 3.3→3.386 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 39 -
Rwork0.293 869 -
obs--100 %

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