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- PDB-6x8i: Caspase-3 in complex with ketomethylene inhibitor reveals tetrahe... -

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Basic information

Entry
Database: PDB / ID: 6x8i
TitleCaspase-3 in complex with ketomethylene inhibitor reveals tetrahedral adduct
Components
  • (Caspase-3) x 2
  • ketomethylene inhibitor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / inhibitor / tetrahedral / complex / 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 / 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: 1.5 Å
AuthorsSolania, A. / Xu, J.H. / Wolan, D.W.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5R21AI112796 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM118382 United States
CitationJournal: To Be Published
Title: Caspase-3 in complex with ketomethylene inhibitor reveals tetrahedral adduct
Authors: Solania, A. / Xu, J.H. / Wolan, D.W.
History
DepositionJun 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Advisory / Author supporting evidence / Database references
Category: database_2 / pdbx_audit_support / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_label_atom_id
Revision 2.1Nov 13, 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
C: Caspase-3
B: Caspase-3
D: Caspase-3
E: ketomethylene inhibitor
F: ketomethylene inhibitor


Theoretical massNumber of molelcules
Total (without water)66,6036
Polymers66,6036
Non-polymers00
Water6,395355
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: previously determined
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15830 Å2
ΔGint-84 kcal/mol
Surface area16500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.652, 85.007, 97.145
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
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 / CASP-3 / Apopain / Cysteine protease CPP32 / CPP-32 / Protein Yama / SREBP cleavage activity 1 / SCA-1


Mass: 19759.344 Da / Num. of mol.: 2 / Fragment: p17 (UNP residues 1-175)
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 Caspase-3 / CASP-3 / Apopain / Cysteine protease CPP32 / CPP-32 / Protein Yama / SREBP cleavage activity 1 / SCA-1


Mass: 12981.756 Da / Num. of mol.: 2 / Fragment: p12 (UNP residues 176-277)
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
#3: Protein/peptide ketomethylene inhibitor


Mass: 560.552 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.: 355 / 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: 2.13 Å3/Da / Density % sol: 42.2 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 1:1 protein : 0.10 M sodium citrate, 0.010 M DTT, 0.02% sodium azide, 10% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.498→50 Å / Num. obs: 90329 / % possible obs: 98.5 % / Redundancy: 5 % / Biso Wilson estimate: 13.68 Å2 / CC1/2: 0.963 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.032 / Rrim(I) all: 0.073 / Net I/σ(I): 0.214
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.675 / Num. unique obs: 4508 / CC1/2: 0.753 / Rpim(I) all: 0.345 / Rrim(I) all: 0.762 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4JJE

4jje


Resolution: 1.5→31.829 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.07
RfactorNum. reflection% reflection
Rfree0.1973 4568 5.06 %
Rwork0.1716 --
obs0.1729 90209 98.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 77.51 Å2 / Biso mean: 17.9099 Å2 / Biso min: 6.19 Å2
Refinement stepCycle: final / Resolution: 1.5→31.829 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3768 0 26 355 4149
Biso mean--15.82 28.68 -
Num. residues----475
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5-1.51530.25771260.232263491
1.5153-1.53310.26881360.2442284799
1.5331-1.55180.25611280.2139285999
1.5518-1.57150.27551590.2104285798
1.5715-1.59210.24911540.193268794
1.5921-1.6140.22631620.184275497
1.614-1.6370.21811610.18312907100
1.637-1.66140.22951450.17872852100
1.6614-1.68740.20411390.17742855100
1.6874-1.71510.23161550.17712896100
1.7151-1.74460.18971540.17782857100
1.7446-1.77640.2161490.17052892100
1.7764-1.81050.20861600.17052870100
1.8105-1.84750.17631490.174286199
1.8475-1.88760.2191630.1741279097
1.8876-1.93160.23461410.1782280297
1.9316-1.97980.17711690.17112871100
1.9798-2.03340.19461480.1662867100
2.0334-2.09320.20911450.1739290699
2.0932-2.16070.21570.16242874100
2.1607-2.23790.18061540.16582911100
2.2379-2.32750.19961590.1691287499
2.3275-2.43340.19991540.1611287198
2.4334-2.56170.20361710.164287799
2.5617-2.72210.14931440.1743290999
2.7221-2.93210.19321740.1833289099
2.9321-3.22690.19971440.1823289498
3.2269-3.69330.19831490.1586287497
3.6933-4.65080.14941640.1419289997
4.6508-31.8290.2141550.1769290493

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