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- PDB-7seo: Crystal Structure of Caspase-3 with Peptide Inhibitor Ac-VDV(DAB)D-CHO -

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Basic information

Entry
Database: PDB / ID: 7seo
TitleCrystal Structure of Caspase-3 with Peptide Inhibitor Ac-VDV(DAB)D-CHO
Components
  • ACE-VAL-ASP-VAL-DAB-ASP
  • Caspase-3 subunit p12
  • Caspase-3 subunit p17
KeywordsAPOPTOSIS / protease / inhibitor / covalent
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 / Apoptosis induced DNA fragmentation / Apoptotic cleavage of cell adhesion proteins / Caspase activation via Dependence Receptors in the absence of ligand / 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 / response to anesthetic / execution phase of apoptosis / negative regulation of cytokine production / positive regulation of amyloid-beta formation / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / pyroptotic inflammatory response / neurotrophin TRK receptor signaling pathway / negative regulation of activated T cell proliferation / response to tumor necrosis factor / negative regulation of cell cycle / T cell homeostasis / B cell homeostasis / cell fate commitment / Pyroptosis / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to X-ray / response to amino acid / response to glucose / response to UV / keratinocyte differentiation / Degradation of the extracellular matrix / striated muscle cell differentiation / intrinsic apoptotic signaling pathway / response to glucocorticoid / protein maturation / erythrocyte differentiation / response to nicotine / hippocampus development / apoptotic signaling pathway / enzyme activator activity / response to hydrogen peroxide / protein catabolic process / sensory perception of sound / regulation of protein stability / protein processing / response to wounding / neuron differentiation / response to estradiol / peptidase activity / positive regulation of neuron apoptotic process / heart development / protease binding / neuron apoptotic process / response to lipopolysaccharide / 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
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 ...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
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.25 Å
AuthorsFuller, J.L. / Finzel, B.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1R01AG062199-0 United States
CitationJournal: Acs Pharmacol Transl Sci / Year: 2022
Title: Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314.
Authors: Bresinsky, M. / Strasser, J.M. / Vallaster, B. / Liu, P. / McCue, W.M. / Fuller, J. / Hubmann, A. / Singh, G. / Nelson, K.M. / Cuellar, M.E. / Wilmot, C.M. / Finzel, B.C. / Ashe, K.H. / ...Authors: Bresinsky, M. / Strasser, J.M. / Vallaster, B. / Liu, P. / McCue, W.M. / Fuller, J. / Hubmann, A. / Singh, G. / Nelson, K.M. / Cuellar, M.E. / Wilmot, C.M. / Finzel, B.C. / Ashe, K.H. / Walters, M.A. / Pockes, S.
History
DepositionSep 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 5, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-3 subunit p17
B: Caspase-3 subunit p12
C: Caspase-3 subunit p17
D: Caspase-3 subunit p12
F: ACE-VAL-ASP-VAL-DAB-ASP
G: ACE-VAL-ASP-VAL-DAB-ASP


Theoretical massNumber of molelcules
Total (without water)56,7116
Polymers56,7116
Non-polymers00
Water1,06359
1
A: Caspase-3 subunit p17
B: Caspase-3 subunit p12
F: ACE-VAL-ASP-VAL-DAB-ASP


Theoretical massNumber of molelcules
Total (without water)28,3553
Polymers28,3553
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5640 Å2
ΔGint-33 kcal/mol
Surface area11020 Å2
MethodPISA
2
C: Caspase-3 subunit p17
D: Caspase-3 subunit p12
G: ACE-VAL-ASP-VAL-DAB-ASP


Theoretical massNumber of molelcules
Total (without water)28,3553
Polymers28,3553
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5410 Å2
ΔGint-33 kcal/mol
Surface area11000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.464, 66.127, 83.468
Angle α, β, γ (deg.)90.000, 90.870, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Caspase-3 subunit p17


Mass: 16524.814 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 PLysS / References: UniProt: P42574
#2: Protein Caspase-3 subunit p12


Mass: 11257.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 PLysS / References: UniProt: P42574
#3: Protein/peptide ACE-VAL-ASP-VAL-DAB-ASP


Mass: 572.609 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.46 Å3/Da / Density % sol: 49.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.3
Details: 15% PEG 6000, 5% Glycerol, 100mM Sodium Citrate (pH 5.3), 10mM DTT, 3mM NaN3

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Jul 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.25→83.46 Å / Num. obs: 8215 / % possible obs: 93.4 % / Redundancy: 2.3 % / Biso Wilson estimate: 48.01 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.074 / Rrim(I) all: 0.122 / Net I/σ(I): 5.2 / Num. measured all: 19027 / Scaling rejects: 14
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.25-3.432.20.207235910760.9420.1560.2613.384.3
10.28-83.462.30.0356382820.9970.0280.0458.894.9

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2H65

2h65


Resolution: 3.25→19.9 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2632 433 5.32 %
Rwork0.189 7712 -
obs0.1928 8145 92.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 109.38 Å2 / Biso mean: 48.5047 Å2 / Biso min: 10.86 Å2
Refinement stepCycle: final / Resolution: 3.25→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3872 0 0 59 3931
Biso mean---37.68 -
Num. residues----480
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.25-3.720.2741610.18342419258089
3.72-4.670.27511410.17622590273194
4.67-19.90.24581310.20332703283496

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