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- PDB-7rn7: Crystal structure of caspase-3 with inhibitor Ac-VD(Aly)VD-CHO -

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Basic information

Entry
Database: PDB / ID: 7rn7
TitleCrystal structure of caspase-3 with inhibitor Ac-VD(Aly)VD-CHO
Components
  • Ac-VD(Aly)VD-CHO
  • Caspase-3 subunit p12
  • Caspase-3 subunit p17
KeywordsHydrolase/Hydrolase Inhibitor / HYDROLASE / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


Stimulation of the cell death response by PAK-2p34 / caspase-3 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / glial cell apoptotic process / positive regulation of pyroptotic inflammatory response / NADE modulates death signalling / luteolysis ...Stimulation of the cell death response by PAK-2p34 / caspase-3 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / glial cell apoptotic process / positive regulation of pyroptotic inflammatory response / NADE modulates death signalling / luteolysis / response to cobalt ion / : / cellular response to staurosporine / death-inducing signaling complex / cyclin-dependent protein serine/threonine kinase inhibitor activity / 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 / death receptor binding / axonal fasciculation / Activation of caspases through apoptosome-mediated cleavage / fibroblast apoptotic process / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / : / epithelial cell apoptotic process / negative regulation of cytokine production / platelet formation / Other interleukin signaling / execution phase of apoptosis / positive regulation of amyloid-beta formation / pyroptotic inflammatory response / negative regulation of B cell proliferation / T cell homeostasis / Apoptotic cleavage of cellular proteins / B cell homeostasis / negative regulation of activated T cell proliferation / neurotrophin TRK receptor signaling pathway / protein maturation / negative regulation of cell cycle / response to X-ray / Pyroptosis / cell fate commitment / response to amino acid / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / response to glucose / response to UV / response to glucocorticoid / keratinocyte differentiation / striated muscle cell differentiation / enzyme activator activity / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / erythrocyte differentiation / apoptotic signaling pathway / hippocampus development / response to nicotine / sensory perception of sound / regulation of protein stability / protein catabolic process / response to hydrogen peroxide / neuron differentiation / protein processing / response to wounding / positive regulation of neuron apoptotic process / response to estradiol / heart development / peptidase activity / protease binding / neuron apoptotic process / response to lipopolysaccharide / aspartic-type endopeptidase activity / learning or memory / response to hypoxia / response to xenobiotic stimulus / cysteine-type endopeptidase activity / neuronal cell body / DNA damage response / protein-containing complex binding / apoptotic process / proteolysis / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
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. ...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: 2.4 Å
AuthorsMcCue, W. / Finzel, B.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)5R01AG062199-03 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
DepositionJul 29, 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 1.3Nov 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 subunit p17
B: Caspase-3 subunit p12
C: Caspase-3 subunit p17
D: Caspase-3 subunit p12
F: Ac-VD(Aly)VD-CHO
G: Ac-VD(Aly)VD-CHO


Theoretical massNumber of molelcules
Total (without water)55,9366
Polymers55,9366
Non-polymers00
Water1,892105
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15440 Å2
ΔGint-87 kcal/mol
Surface area17090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.509, 68.041, 82.493
Angle α, β, γ (deg.)90.000, 90.608, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Caspase-3 subunit p17


Mass: 16067.288 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 BL21(DE3) (bacteria) / 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 BL21(DE3) (bacteria) / References: UniProt: P42574
#3: Protein/peptide Ac-VD(Aly)VD-CHO


Mass: 642.699 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.: 105 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 50.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 16% PEG 6000, 5% glycerol, 100 mM sodium citrate pH 6.5, and 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Apr 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→52.49 Å / Num. obs: 21724 / % possible obs: 98.6 % / Redundancy: 3 % / CC1/2: 0.959 / Rmerge(I) obs: 0.182 / Rpim(I) all: 0.126 / Rrim(I) all: 0.223 / Net I/σ(I): 4.4 / Num. measured all: 64359 / Scaling rejects: 102
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.518 / Num. unique obs: 3170 / CC1/2: 0.712 / Rpim(I) all: 0.37 / Rrim(I) all: 0.64 / % possible all: 98.5

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.19.2refinement
PDB_EXTRACT3.27data extraction
AutoProcessdata reduction
PHASERphasing
JDirectordata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2H65

2h65


Resolution: 2.4→43.28 Å / SU ML: 0.3253 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.008
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2515 1107 5.1 %
Rwork0.1878 20587 -
obs0.1911 21694 98.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.12 Å2
Refinement stepCycle: LAST / Resolution: 2.4→43.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3788 0 0 105 3893
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00833885
X-RAY DIFFRACTIONf_angle_d1.07775230
X-RAY DIFFRACTIONf_chiral_restr0.0559573
X-RAY DIFFRACTIONf_plane_restr0.0061670
X-RAY DIFFRACTIONf_dihedral_angle_d20.74533
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.510.31551580.22762534X-RAY DIFFRACTION98.03
2.51-2.640.33041210.22222610X-RAY DIFFRACTION99.16
2.64-2.810.30181460.22632567X-RAY DIFFRACTION99.6
2.81-3.020.32511230.22772594X-RAY DIFFRACTION99.31
3.02-3.330.25591570.21172553X-RAY DIFFRACTION99.01
3.33-3.810.24481180.17332598X-RAY DIFFRACTION98.55
3.81-4.80.19731440.14572519X-RAY DIFFRACTION96.45
4.8-43.280.221400.17332612X-RAY DIFFRACTION96.94

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