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- PDB-6x8k: Caspase-3 in complex with elongated ketomethylene inhibitor -

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Basic information

Entry
Database: PDB / ID: 6x8k
TitleCaspase-3 in complex with elongated ketomethylene inhibitor
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 / 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 / cellular response to staurosporine / death-inducing signaling complex / cyclin-dependent protein serine/threonine kinase inhibitor activity / response to anesthetic / 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 / death receptor binding / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / axonal fasciculation / regulation of synaptic vesicle cycle / fibroblast apoptotic process / epithelial cell apoptotic process / Other interleukin signaling / platelet formation / negative regulation of cytokine production / positive regulation of amyloid-beta formation / execution phase of apoptosis / negative regulation of B cell proliferation / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / negative regulation of activated T cell proliferation / T cell homeostasis / neurotrophin TRK receptor signaling pathway / B cell homeostasis / negative regulation of cell cycle / response to tumor necrosis factor / cell fate commitment / response to amino acid / response to X-ray / Pyroptosis / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to glucose / response to glucocorticoid / response to UV / keratinocyte differentiation / striated muscle cell differentiation / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / protein maturation / enzyme activator activity / erythrocyte differentiation / hippocampus development / response to nicotine / apoptotic signaling pathway / sensory perception of sound / protein catabolic process / regulation of protein stability / protein processing / response to hydrogen peroxide / response to wounding / neuron differentiation / positive regulation of neuron apoptotic process / response to estradiol / peptidase activity / 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: 2.17 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 elongated ketomethylene inhibitor
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: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
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_main_chain_plane / 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.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Oct 23, 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
B: Caspase-3
C: Caspase-3
D: Caspase-3
E: ketomethylene inhibitor
F: ketomethylene inhibitor


Theoretical massNumber of molelcules
Total (without water)67,0306
Polymers67,0306
Non-polymers00
Water2,360131
1
A: Caspase-3
C: Caspase-3
E: ketomethylene inhibitor

A: Caspase-3
C: Caspase-3
E: ketomethylene inhibitor


Theoretical massNumber of molelcules
Total (without water)67,0306
Polymers67,0306
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area15230 Å2
ΔGint-86 kcal/mol
Surface area16840 Å2
MethodPISA
2
B: Caspase-3
D: Caspase-3
F: ketomethylene inhibitor

B: Caspase-3
D: Caspase-3
F: ketomethylene inhibitor


Theoretical massNumber of molelcules
Total (without water)67,0306
Polymers67,0306
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area15640 Å2
ΔGint-84 kcal/mol
Surface area17020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.863, 96.908, 100.460
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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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: 773.786 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.: 131 / 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: 2.54 Å3/Da / Density % sol: 51.51 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 1:1 protein : 0.10 M sodium citrate, 0.010 M DTT, 0.02% sodium azide, 12% 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-F / Detector: PIXEL / Date: May 16, 2019
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: 2.17→50 Å / Num. obs: 37653 / % possible obs: 97.5 % / Redundancy: 4.8 % / Biso Wilson estimate: 23.41 Å2 / Rmerge(I) obs: 0.202 / Rpim(I) all: 0.1 / Rrim(I) all: 0.227 / Χ2: 1.026 / Net I/σ(I): 10.7 / Num. measured all: 182390
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.17-2.214.11.34918450.2510.7231.540.72197
2.21-2.254.11.39218420.3430.7411.5850.59396.9
2.25-2.294.61.04618300.2460.5461.1881.16797.1
2.29-2.344.80.89219200.540.4471.0031.23499.1
2.34-2.394.90.69918480.5890.3460.7840.82898.9
2.39-2.444.90.62918770.8530.3040.7020.84798
2.44-2.514.90.55818930.7710.2710.6230.88598.4
2.51-2.574.90.49518560.810.2410.5531.01198.5
2.57-2.654.90.42218880.8450.2060.4730.91498.2
2.65-2.734.90.38418550.8910.1860.4290.95397.2
2.73-2.834.50.31918500.9080.160.3591.38297.2
2.83-2.954.60.27818550.9450.1390.3131.5295.9
2.95-3.085.20.20218990.9640.0940.2241.49598.5
3.08-3.245.30.16619040.9670.0780.1841.14398.8
3.24-3.445.20.14118830.9780.0670.1561.04198.7
3.44-3.715.20.11819260.9780.0560.1311.0697.8
3.71-4.084.80.11418890.9770.0560.1280.85496.7
4.08-4.6750.09418860.9850.0450.1050.99596.1
4.67-5.895.30.08419500.9910.0390.0930.98797.8
5.89-504.90.12519570.9660.0640.1410.77293.1

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4JJE

4jje


Resolution: 2.17→39.815 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.263 1833 5.11 %
Rwork0.2206 34018 -
obs0.2228 35851 97.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 75.24 Å2 / Biso mean: 28.5231 Å2 / Biso min: 5.38 Å2
Refinement stepCycle: final / Resolution: 2.17→39.815 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3765 0 0 131 3896
Biso mean---30 -
Num. residues----478
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.17-2.22870.32911360.2635253996
2.2287-2.29430.34151460.2661263199
2.2943-2.36830.32361600.2475257899
2.3683-2.45290.32371400.2355259198
2.4529-2.55110.26741300.2323261498
2.5511-2.66720.30531410.2305259998
2.6672-2.80780.29881340.245255096
2.8078-2.98370.27821230.2273265198
2.9837-3.21390.2721240.2326265399
3.2139-3.53720.24051390.2155265098
3.5372-4.04860.22711710.1993258096
4.0486-5.09910.22261430.1809266697
5.0991-39.8150.2361460.2207271695

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