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- PDB-7rn9: Crystal structure of caspase-3 with inhibitor Ac-VDFVD-CHO -

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Basic information

Entry
Database: PDB / ID: 7rn9
TitleCrystal structure of caspase-3 with inhibitor Ac-VDFVD-CHO
Components
  • Ac-VDFVD-CHO
  • Caspase-3 subunit p12
  • Caspase-3 subunit p17
KeywordsHYDROLASE / Hydrolase/Hydrolase Inhibitor
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 / protein processing / regulation of protein stability / 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 / cytosol / cytoplasm
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: 1.67 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 2.0Jun 28, 2023Group: Advisory / Database references ...Advisory / Database references / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: chem_comp / entity ...chem_comp / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_src_syn / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues / pdbx_validate_close_contact / struct_conn / struct_ref_seq
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.gene_src_common_name / _pdbx_entity_src_syn.pdbx_end_seq_num / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_end
Revision 2.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 3.0Feb 7, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Polymer sequence / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / entity / entity_poly / entity_poly_seq / pdbx_poly_seq_scheme / struct_conn
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_comp_id / _atom_site.group_PDB / _atom_site.label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly_seq.mon_id / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id
Revision 3.1Nov 6, 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: Ac-VDFVD-CHO
G: Ac-VDFVD-CHO


Theoretical massNumber of molelcules
Total (without water)55,8586
Polymers55,8586
Non-polymers00
Water5,206289
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15410 Å2
ΔGint-87 kcal/mol
Surface area16960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.472, 85.195, 97.610
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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-VDFVD-CHO


Mass: 603.664 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.: 289 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.47 Å3/Da / Density % sol: 50.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 15% PEG 6000, 5% glycerol (v:v), 100 mM sodium citrate pH 5.3, 10 mM DTT, and 30 mM NaN3

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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: Mar 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.67→64.19 Å / Num. obs: 64636 / % possible obs: 97.3 % / Redundancy: 6.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.028 / Rrim(I) all: 0.072 / Net I/σ(I): 14.3 / Num. measured all: 412048 / Scaling rejects: 10
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
1.67-1.763.60.4173145787220.9140.2410.4842.691.7
5.27-64.196.90.0481604823140.9980.0190.05228.999.9

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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: 1.67→42.35 Å / SU ML: 0.192 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.5003
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2099 3280 5.09 %
Rwork0.1831 61195 -
obs0.1845 64475 97.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.23 Å2
Refinement stepCycle: LAST / Resolution: 1.67→42.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3803 0 0 289 4092
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00773923
X-RAY DIFFRACTIONf_angle_d0.92585279
X-RAY DIFFRACTIONf_chiral_restr0.0598570
X-RAY DIFFRACTIONf_plane_restr0.0052676
X-RAY DIFFRACTIONf_dihedral_angle_d18.6703527
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.67-1.690.33391290.27942322X-RAY DIFFRACTION86.3
1.69-1.720.31771210.2572448X-RAY DIFFRACTION89.39
1.72-1.750.25691270.24372566X-RAY DIFFRACTION94.59
1.75-1.780.24221430.21772655X-RAY DIFFRACTION97.93
1.78-1.810.2531270.20822690X-RAY DIFFRACTION99.75
1.81-1.840.24231480.20112704X-RAY DIFFRACTION99.72
1.84-1.880.22621550.19322704X-RAY DIFFRACTION99.62
1.88-1.910.22721180.19792238X-RAY DIFFRACTION98.04
1.92-1.970.23841500.19612429X-RAY DIFFRACTION99.08
1.97-2.010.2331340.192752X-RAY DIFFRACTION99.9
2.01-2.070.24731460.19382694X-RAY DIFFRACTION99.82
2.07-2.130.22551520.1942744X-RAY DIFFRACTION99.93
2.13-2.20.20421660.18222682X-RAY DIFFRACTION99.86
2.2-2.280.19081560.18042724X-RAY DIFFRACTION99.83
2.28-2.370.2141470.17662729X-RAY DIFFRACTION99.86
2.37-2.480.20941400.17562737X-RAY DIFFRACTION99.83
2.48-2.610.20171410.18822746X-RAY DIFFRACTION99.93
2.61-2.770.20871410.20092758X-RAY DIFFRACTION100
2.77-2.980.24351530.19752740X-RAY DIFFRACTION99.9
2.98-3.280.22211390.19542793X-RAY DIFFRACTION99.76
3.28-3.760.19631480.16682653X-RAY DIFFRACTION95.27
3.76-4.730.18121430.14472747X-RAY DIFFRACTION97.5
4.74-42.350.17141560.17442940X-RAY DIFFRACTION99.58

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