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- PDB-3dej: Crystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-tri... -

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Basic information

Entry
Database: PDB / ID: 3dej
TitleCrystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative Inhibitors
ComponentsCaspase-3Caspase 3
KeywordsHydrolase / Apoptosis / Caspase-3 / Isoquinoline-1 / 3 / 4-trione derivatives / Inactivation / protein-inhibitor complex / Cytoplasm / Phosphoprotein / Polymorphism / Protease / S-nitrosylation / Thiol protease / Zymogen
Function / homology
Function and homology information


caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis ...caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / cyclin-dependent protein serine/threonine kinase inhibitor activity / cellular response to staurosporine / Apoptosis induced DNA fragmentation / Apoptotic cleavage of cell adhesion proteins / cysteine-type endopeptidase activity involved in execution phase of apoptosis / Caspase activation via Dependence Receptors in the absence of ligand / death receptor binding / SMAC, XIAP-regulated apoptotic response / axonal fasciculation / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / cysteine-type endopeptidase activity involved in apoptotic process / fibroblast apoptotic process / execution phase of apoptosis / negative regulation of cytokine production / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / positive regulation of amyloid-beta formation / pyroptotic inflammatory response / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / T cell homeostasis / negative regulation of activated T cell proliferation / neurotrophin TRK receptor signaling pathway / B cell homeostasis / protein maturation / negative regulation of cell cycle / response to X-ray / Caspase-mediated cleavage of cytoskeletal proteins / regulation of macroautophagy / response to amino acid / cell fate commitment / Pyroptosis / response to tumor necrosis factor / response to glucose / response to UV / response to glucocorticoid / keratinocyte differentiation / striated muscle cell differentiation / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / erythrocyte differentiation / response to nicotine / apoptotic signaling pathway / hippocampus development / sensory perception of sound / protein catabolic process / regulation of protein stability / response to hydrogen peroxide / protein processing / neuron differentiation / response to wounding / positive regulation of neuron apoptotic process / response to estradiol / heart development / peptidase activity / neuron apoptotic process / protease binding / response to lipopolysaccharide / aspartic-type endopeptidase activity / response to hypoxia / learning or memory / response to xenobiotic stimulus / positive regulation of apoptotic process / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / proteolysis / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain ...Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-RXC / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsWu, J. / Du, J. / Li, J. / Ding, J.
CitationJournal: J.Biol.Chem. / Year: 2008
Title: Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species
Authors: Du, J.-Q. / Wu, J. / Zhang, H.-J. / Zhang, Y.-H. / Qiu, B.-Y. / Wu, F. / Chen, Y.-H. / Li, J.-Y. / Nan, F.-J. / Ding, J.-P. / Li, J.
History
DepositionJun 10, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 2, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Nov 1, 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_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-3
B: Caspase-3
C: Caspase-3
D: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6675
Polymers114,2664
Non-polymers4011
Water2,234124
1
A: Caspase-3
B: Caspase-3


Theoretical massNumber of molelcules
Total (without water)57,1332
Polymers57,1332
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-18 kcal/mol
Surface area18780 Å2
MethodPISA
2
C: Caspase-3
D: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5343
Polymers57,1332
Non-polymers4011
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4000 Å2
ΔGint-22 kcal/mol
Surface area19150 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10220 Å2
ΔGint-47 kcal/mol
Surface area36010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.433, 96.675, 180.446
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Caspase-3 / Caspase 3 / CASP-3 / Apopain / Cysteine protease CPP32 / Yama protein / CPP-32 / SREBP cleavage activity 1 / ...CASP-3 / Apopain / Cysteine protease CPP32 / Yama protein / CPP-32 / SREBP cleavage activity 1 / SCA-1 / Caspase-3 subunit p17 / Caspase-3 subunit p12


Mass: 28566.500 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET32b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P42574, caspase-3
#2: Chemical ChemComp-RXC / (1S)-1-(3-chlorophenyl)-2-oxo-2-[(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]ethyl acetate


Mass: 400.769 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H13ClN2O6
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 124 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE INHIBITOR WAS SYNTHESIZED AT CHINESE NATIONAL CENTER FOR DRUG SCREENING
Sequence details190TH RESIDUE IN ALL CHAINS IS ASP AND IS A NATURAL VARIANT FOR CASP3_HUMAN.

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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: 2.5 Å3/Da / Density % sol: 50.75 % / Mosaicity: 0.494 °
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 4-6% polyethylene glycol 6000, 0.1M HEPES pH 7.6, 20mM L-cysteine, 5% glycerol, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jun 23, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 35800 / % possible obs: 99.2 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.121 / Χ2: 1.085 / Net I/σ(I): 7.6
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 3 % / Rmerge(I) obs: 0.482 / Num. unique all: 3338 / Χ2: 0.385 / % possible all: 94.1

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.1.24refinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1GFW

1gfw


Resolution: 2.6→46.45 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.905 / SU B: 12.196 / SU ML: 0.257 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.346 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.274 1785 5 %RANDOM
Rwork0.214 ---
obs0.217 35739 99.18 %-
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: 62.071 Å2
Baniso -1Baniso -2Baniso -3
1-1.31 Å20 Å20 Å2
2---0.97 Å20 Å2
3----0.34 Å2
Refinement stepCycle: LAST / Resolution: 2.6→46.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7549 0 28 124 7701
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0217736
X-RAY DIFFRACTIONr_angle_refined_deg1.2421.95310404
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2635921
X-RAY DIFFRACTIONr_chiral_restr0.0860.21119
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025809
X-RAY DIFFRACTIONr_nbd_refined0.220.23524
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1270.2330
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1520.221
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0840.24
X-RAY DIFFRACTIONr_mcbond_it1.6261.54618
X-RAY DIFFRACTIONr_mcangle_it3.2127455
X-RAY DIFFRACTIONr_scbond_it3.55933118
X-RAY DIFFRACTIONr_scangle_it6.2224.52949
X-RAY DIFFRACTIONr_rigid_bond_restr1.90127736
X-RAY DIFFRACTIONr_sphericity_free1.7442124
X-RAY DIFFRACTIONr_sphericity_bonded1.08627578
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.391 135
Rwork0.322 2295
all-2430

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