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- PDB-6px9: Crystal structure of procaspase-8 in complex with covalent small ... -

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Basic information

Entry
Database: PDB / ID: 6px9
TitleCrystal structure of procaspase-8 in complex with covalent small molecule inhibitor 63-R
ComponentsCaspase-8
KeywordsHYDROLASE/HYDROLASE INHIBITOR / zymogen / procaspase / covalent inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


caspase-8 / death effector domain binding / FasL/ CD95L signaling / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / TRAIL signaling / CD95 death-inducing signaling complex / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / TRAIL-activated apoptotic signaling pathway ...caspase-8 / death effector domain binding / FasL/ CD95L signaling / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / TRAIL signaling / CD95 death-inducing signaling complex / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / TRAIL-activated apoptotic signaling pathway / Activation, myristolyation of BID and translocation to mitochondria / TRIF-mediated programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / Caspase activation via Death Receptors in the presence of ligand / positive regulation of macrophage differentiation / self proteolysis / response to cobalt ion / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / CLEC7A/inflammasome pathway / negative regulation of necroptotic process / response to anesthetic / regulation of tumor necrosis factor-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / natural killer cell activation / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / execution phase of apoptosis / regulation of innate immune response / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / : / B cell activation / positive regulation of proteolysis / macrophage differentiation / response to tumor necrosis factor / extrinsic apoptotic signaling pathway via death domain receptors / Caspase-mediated cleavage of cytoskeletal proteins / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / cysteine-type peptidase activity / regulation of cytokine production / protein maturation / proteolysis involved in protein catabolic process / T cell activation / positive regulation of interleukin-1 beta production / Regulation of NF-kappa B signaling / apoptotic signaling pathway / Regulation of TNFR1 signaling / NOD1/2 Signaling Pathway / protein processing / Regulation of necroptotic cell death / cellular response to mechanical stimulus / positive regulation of neuron apoptotic process / response to estradiol / lamellipodium / peptidase activity / heart development / cell body / scaffold protein binding / angiogenesis / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / positive regulation of canonical NF-kappaB signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of apoptotic process / cysteine-type endopeptidase activity / apoptotic process / ubiquitin protein ligase binding / protein-containing complex binding / protein-containing complex / mitochondrion / proteolysis / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Caspase-8 / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death effector domain / Rossmann fold - #1460 / 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-8 / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Death effector domain / Rossmann fold - #1460 / 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 / Death-like domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-63R / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 Å
AuthorsXu, J.H. / Wolan, D.W.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM118382 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM069832 United States
Department of Energy (DOE, United States)DE-FC02-02ER63421 United States
CitationJournal: Acs Chem.Biol. / Year: 2020
Title: Integrative X-ray Structure and Molecular Modeling for the Rationalization of Procaspase-8 Inhibitor Potency and Selectivity.
Authors: Xu, J.H. / Eberhardt, J. / Hill-Payne, B. / Gonzalez-Paez, G.E. / Castellon, J.O. / Cravatt, B.F. / Forli, S. / Wolan, D.W. / Backus, K.M.
History
DepositionJul 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 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-8
B: Caspase-8
C: Caspase-8
D: Caspase-8
E: Caspase-8
F: Caspase-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)187,5857
Polymers187,1786
Non-polymers4081
Water543
1
A: Caspase-8
B: Caspase-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,8003
Polymers62,3932
Non-polymers4081
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2690 Å2
ΔGint-8 kcal/mol
Surface area16720 Å2
MethodPISA
2
C: Caspase-8
D: Caspase-8


Theoretical massNumber of molelcules
Total (without water)62,3932
Polymers62,3932
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2710 Å2
ΔGint-12 kcal/mol
Surface area16830 Å2
MethodPISA
3
E: Caspase-8
F: Caspase-8


Theoretical massNumber of molelcules
Total (without water)62,3932
Polymers62,3932
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-15 kcal/mol
Surface area17010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.311, 101.311, 175.547
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

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Components

#1: Protein
Caspase-8 / CASP-8 / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / FADD-homologous ICE/ced-3- ...CASP-8 / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / FADD-homologous ICE/ced-3-like protease / FADD-like ICE / FLICE / ICE-like apoptotic protease 5 / MORT1-associated ced-3 homolog / MACH


Mass: 31196.271 Da / Num. of mol.: 6 / Fragment: UNP residues 276-538 / Mutation: D374A, D384A, C409S, C433S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP8, MCH5 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14790, caspase-8
#2: Chemical ChemComp-63R / N-{(3R)-1-[4-(morpholin-4-yl)benzene-1-carbonyl]piperidin-3-yl}-N-phenylacetamide


Mass: 407.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N3O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.78 Å3/Da / Density % sol: 55.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1 M imidazole, pH 8.0, 1.0 M sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 12, 2016
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: 2.877→50 Å / Num. obs: 45476 / % possible obs: 99.5 % / Redundancy: 4.5 % / CC1/2: 0.679 / Rmerge(I) obs: 0.297 / Rpim(I) all: 0.156 / Rrim(I) all: 0.336 / Net I/σ(I): 8.1
Reflection shellResolution: 2.88→2.93 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.32 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 2243 / CC1/2: 0.174 / Rpim(I) all: 0.71 / Rrim(I) all: 1.5 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4JJ7

4jj7


Resolution: 2.88→35.1 Å / SU ML: 0.9 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 46.53
RfactorNum. reflection% reflection
Rfree0.3665 2253 4.97 %
Rwork0.2856 --
obs0.2894 45343 99.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 50.63 Å2 / Biso mean: 44.0086 Å2 / Biso min: 37.46 Å2
Refinement stepCycle: final / Resolution: 2.88→35.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9841 0 30 3 9874
Biso mean--42.6 39.69 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00310092
X-RAY DIFFRACTIONf_angle_d0.67713671
X-RAY DIFFRACTIONf_chiral_restr0.0441532
X-RAY DIFFRACTIONf_plane_restr0.0051764
X-RAY DIFFRACTIONf_dihedral_angle_d3.658004
LS refinement shellResolution: 2.88→2.94 Å
RfactorNum. reflection% reflection
Rfree0.494 --
Rwork0.442 --
obs-2630 97.7 %

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