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- PDB-4ehn: Allosteric Modulation of Caspase-3 through Mutagenesis -

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Basic information

Entry
Database: PDB / ID: 4ehn
TitleAllosteric Modulation of Caspase-3 through Mutagenesis
Components
  • ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR
  • Caspase-3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / caspase / apoptosis / allosteric inhibition / protein ensembles / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


caspase-3 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / cellular response to staurosporine / cyclin-dependent protein serine/threonine kinase inhibitor activity / death-inducing signaling complex / Caspase activation via Dependence Receptors in the absence of ligand / Apoptotic cleavage of cell adhesion proteins / Apoptosis induced DNA fragmentation / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / axonal fasciculation / regulation of synaptic vesicle cycle / death receptor binding / fibroblast apoptotic process / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / execution phase of apoptosis / negative regulation of cytokine production / response to anesthetic / positive regulation of amyloid-beta formation / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / negative regulation of activated T cell proliferation / neurotrophin TRK receptor signaling pathway / negative regulation of cell cycle / T cell homeostasis / B cell homeostasis / response to tumor necrosis factor / pyroptotic inflammatory response / Pyroptosis / cell fate commitment / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to amino acid / response to X-ray / response to insulin-like growth factor stimulus / response to glucose / response to UV / keratinocyte differentiation / Degradation of the extracellular matrix / striated muscle cell differentiation / swimming behavior / intrinsic apoptotic signaling pathway / response to glucocorticoid / erythrocyte differentiation / response to nicotine / protein maturation / hippocampus development / protein catabolic process / apoptotic signaling pathway / response to hydrogen peroxide / sensory perception of sound / regulation of protein stability / protein processing / response to wounding / enzyme activator activity / neuron differentiation / response to estradiol / peptidase activity / positive regulation of neuron apoptotic process / heart development / protease binding / neuron apoptotic process / response to lipopolysaccharide / response to ethanol / aspartic-type endopeptidase activity / learning or memory / response to hypoxia / postsynaptic density / response to xenobiotic stimulus / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / glutamatergic synapse / proteolysis / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Rossmann fold - #1460 / Peptidase C14 family / 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 ...Rossmann fold - #1460 / Peptidase C14 family / 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
Ac-Asp-Glu-Val-Asp-CMK / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsWalters, J. / Schipper, J.L. / Swartz, P.D. / Mattos, C. / Clark, A.C.
CitationJournal: Biosci.Rep. / Year: 2012
Title: Allosteric modulation of caspase 3 through mutagenesis.
Authors: Walters, J. / Schipper, J.L. / Swartz, P. / Mattos, C. / Clark, A.C.
History
DepositionApr 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 18, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Nov 15, 2017Group: Advisory / Refinement description / Source and taxonomy
Category: pdbx_entity_src_syn / pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Oct 16, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_ref_seq_dif
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_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-3
B: ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)32,1082
Polymers32,1082
Non-polymers00
Water4,702261
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint2 kcal/mol
Surface area11180 Å2
MethodPISA
2
A: Caspase-3
B: ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR

A: Caspase-3
B: ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)64,2164
Polymers64,2164
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_656-x+1,y,-z+11
Buried area6680 Å2
ΔGint-8 kcal/mol
Surface area18050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.890, 85.522, 96.341
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-527-

HOH

21A-645-

HOH

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Components

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


Mass: 31572.883 Da / Num. of mol.: 1 / Mutation: E124A,Y197C,V266H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Production host: Escherichia coli (E. coli) / References: UniProt: P42574, caspase-3
#2: Protein/peptide ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR


Type: Peptide-like / Class: Inhibitor / Mass: 534.946 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: Ac-Asp-Glu-Val-Asp-CMK
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.25 Å3/Da / Density % sol: 45.26 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 22, 2008
RadiationMonochromator: Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.69→35 Å / Num. all: 32744 / Num. obs: 31764 / % possible obs: 98.7 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3
Reflection shell
Resolution (Å)Diffraction-ID% possible all
2.13-2.291100
2-2.131100
1.9-21100
1.82-1.9199.7
1.75-1.82197.3
1.69-1.75190.3

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Processing

Software
NameVersionClassification
MAR345data collection
SERGUIdata collection
PHENIXmodel building
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.69→33.994 Å / SU ML: 0.16 / σ(F): 1.34 / Phase error: 17.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1919 1995 6.29 %Random
Rwork0.1599 ---
all0.1919 32744 --
obs0.1619 31715 98.47 %-
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 38.223 Å2 / ksol: 0.36 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.3739 Å20 Å2-0 Å2
2--4.5439 Å2-0 Å2
3----4.9178 Å2
Refinement stepCycle: LAST / Resolution: 1.69→33.994 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1905 0 0 261 2166
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072043
X-RAY DIFFRACTIONf_angle_d1.1242766
X-RAY DIFFRACTIONf_dihedral_angle_d13.206781
X-RAY DIFFRACTIONf_chiral_restr0.079297
X-RAY DIFFRACTIONf_plane_restr0.005358
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.73250.27961250.23271857X-RAY DIFFRACTION88
1.7325-1.77930.23821360.20012017X-RAY DIFFRACTION95
1.7793-1.83170.19591400.17932089X-RAY DIFFRACTION98
1.8317-1.89080.20031430.16722109X-RAY DIFFRACTION100
1.8908-1.95840.21971420.16262136X-RAY DIFFRACTION100
1.9584-2.03680.22851450.16122150X-RAY DIFFRACTION100
2.0368-2.12940.18931430.17242125X-RAY DIFFRACTION100
2.1294-2.24170.19011440.15912152X-RAY DIFFRACTION100
2.2417-2.38210.16791430.15012140X-RAY DIFFRACTION100
2.3821-2.5660.18191430.1562141X-RAY DIFFRACTION100
2.566-2.82410.21931470.16642173X-RAY DIFFRACTION100
2.8241-3.23250.20481430.16492165X-RAY DIFFRACTION100
3.2325-4.07150.16041480.13832201X-RAY DIFFRACTION100
4.0715-34.00110.18211530.15582265X-RAY DIFFRACTION99

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