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

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Basic information

Entry
Database: PDB / ID: 4ehk
TitleAllosteric Modulation of Caspase-3 through Mutagenesis
Components
  • ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR
  • Caspase-3Caspase 3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / caspase / apoptosis / allosteric inhibition / protein ensembles / HYDROLASE-HYDROLASE INHIBITOR complex
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
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: 1.668 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: Refinement description / Source and taxonomy / Category: pdbx_entity_src_syn / software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)64,1384
Polymers64,1384
Non-polymers00
Water7,224401
1
A: Caspase-3
B: ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)32,0692
Polymers32,0692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint2 kcal/mol
Surface area10870 Å2
MethodPISA
2
C: Caspase-3
D: ACE-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)32,0692
Polymers32,0692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint2 kcal/mol
Surface area10920 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6500 Å2
ΔGint-16 kcal/mol
Surface area17660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.820, 96.775, 69.176
Angle α, β, γ (deg.)90.00, 127.39, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-538-

HOH

21A-602-

HOH

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Components

#1: Protein Caspase-3 / 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: 31533.867 Da / Num. of mol.: 2 / Mutation: E124A,Y197C
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.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: Ac-Asp-Glu-Val-Asp-CMK
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 401 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 46.88 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Protein solution: 8 mg/ml protein in 10 mM Tris-HCl, pH 8.5, 10 mM DTT, and 3 mM NaN3. Reservoir solution: 100 mM sodium citrate, pH 5.0, 3 mM NaN3, 10 mM DTT, and 10% 16% PEG 6000. Drop: ...Details: Protein solution: 8 mg/ml protein in 10 mM Tris-HCl, pH 8.5, 10 mM DTT, and 3 mM NaN3. Reservoir solution: 100 mM sodium citrate, pH 5.0, 3 mM NaN3, 10 mM DTT, and 10% 16% PEG 6000. Drop: 4ul protein Solution: 4 ul reservoir solution, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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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: Dec 10, 2007
RadiationMonochromator: Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.668→35 Å / Num. all: 86268 / Num. obs: 64962 / % possible obs: 97.9 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3
Reflection shell
Resolution (Å)Diffraction-ID% possible all
2.12-2.28198.5
1.99-2.12198.4
1.89-1.99198
1.81-1.89197.9
1.74-1.81197.8
1.68-1.74197.2

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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: 1.668→27.481 Å / SU ML: 0.18 / σ(F): 1.33 / Phase error: 24.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2295 2002 3.09 %Random
Rwork0.196 ---
all0.2295 86268 --
obs0.197 64820 97.11 %-
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 61.183 Å2 / ksol: 0.386 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.0324 Å2-0 Å22.9419 Å2
2---5.6977 Å20 Å2
3---5.7301 Å2
Refinement stepCycle: LAST / Resolution: 1.668→27.481 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3764 0 0 401 4165
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073908
X-RAY DIFFRACTIONf_angle_d1.1515270
X-RAY DIFFRACTIONf_dihedral_angle_d13.081461
X-RAY DIFFRACTIONf_chiral_restr0.085574
X-RAY DIFFRACTIONf_plane_restr0.004676
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.668-1.70980.31531340.26344062X-RAY DIFFRACTION88
1.7098-1.7560.28721410.25064470X-RAY DIFFRACTION97
1.756-1.80760.29591400.23034519X-RAY DIFFRACTION98
1.8076-1.8660.25781360.23364528X-RAY DIFFRACTION98
1.866-1.93270.3451530.2974446X-RAY DIFFRACTION97
1.9327-2.010.27231400.22074522X-RAY DIFFRACTION98
2.01-2.10150.22591490.19734551X-RAY DIFFRACTION98
2.1015-2.21220.23741460.20274494X-RAY DIFFRACTION98
2.2122-2.35070.24931400.21854515X-RAY DIFFRACTION98
2.3507-2.53210.19971400.1884573X-RAY DIFFRACTION99
2.5321-2.78670.21961490.19014557X-RAY DIFFRACTION99
2.7867-3.18940.2191460.19244569X-RAY DIFFRACTION99
3.1894-4.01640.19761430.16434538X-RAY DIFFRACTION98
4.0164-27.48460.20881450.17454474X-RAY DIFFRACTION95

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