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- PDB-3kjq: Caspase 8 with covalent inhibitor -

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Basic information

Entry
Database: PDB / ID: 3kjq
TitleCaspase 8 with covalent inhibitor
Components(Caspase-8Caspase 8) x 2
KeywordsHYDROLASE / caspase 8 / Apoptosis / kinetics / Peptidomimetic Inhibitor / urazole / Disease mutation / Phosphoprotein / Protease / Thiol protease / Zymogen / Allosteric
Function / homology
Function and homology information


caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / TRAIL signaling / CD95 death-inducing signaling complex / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria ...caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / TRAIL signaling / CD95 death-inducing signaling complex / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / TRAIL-activated apoptotic signaling pathway / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / Caspase activation via Death Receptors in the presence of ligand / positive regulation of macrophage differentiation / self proteolysis / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / negative regulation of necroptotic process / natural killer cell activation / CLEC7A/inflammasome pathway / regulation of tumor necrosis factor-mediated signaling pathway / activation of cysteine-type endopeptidase activity / tumor necrosis factor receptor binding / death receptor binding / cysteine-type endopeptidase activity involved in apoptotic process / TNFR1-induced proapoptotic signaling / execution phase of apoptosis / RIPK1-mediated regulated necrosis / B cell activation / regulation of innate immune response / pyroptotic inflammatory response / Apoptotic cleavage of cellular proteins / positive regulation of proteolysis / macrophage differentiation / protein maturation / cellular response to organic cyclic compound / extrinsic apoptotic signaling pathway via death domain receptors / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / cysteine-type peptidase activity / negative regulation of canonical NF-kappaB signal transduction / extrinsic apoptotic signaling pathway / regulation of cytokine production / T cell activation / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / Regulation of NF-kappa B signaling / apoptotic signaling pathway / Regulation of TNFR1 signaling / NOD1/2 Signaling Pathway / Regulation of necroptotic cell death / cellular response to mechanical stimulus / positive regulation of neuron apoptotic process / response to estradiol / lamellipodium / cell body / heart development / peptidase activity / scaffold protein binding / angiogenesis / response to ethanol / positive regulation of canonical NF-kappaB signal transduction / mitochondrial outer membrane / response to lipopolysaccharide / 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 / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Caspase-like / Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 ...Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Caspase-like / 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 / Alpha-Beta Plaits / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-B94 / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsKamtekar, S. / Watt, W. / Finzel, B.C. / Harris, M.S. / Blinn, J. / Wang, Z. / Tomasselli, A.G.
CitationJournal: Biochim.Biophys.Acta / Year: 2010
Title: Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors.
Authors: Wang, Z. / Watt, W. / Brooks, N.A. / Harris, M.S. / Urban, J. / Boatman, D. / McMillan, M. / Kahn, M. / Heinrikson, R.L. / Finzel, B.C. / Wittwer, A.J. / Blinn, J. / Kamtekar, S. / Tomasselli, A.G.
History
DepositionNov 3, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7254
Polymers29,5412
Non-polymers1,1842
Water2,630146
1
A: Caspase-8
B: Caspase-8
hetero molecules

A: Caspase-8
B: Caspase-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,4518
Polymers59,0834
Non-polymers2,3684
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+1/31
Buried area13780 Å2
ΔGint-90 kcal/mol
Surface area19370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.974, 63.974, 130.847
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Caspase-8 / Caspase 8 / CASP-8 / ICE-like apoptotic protease 5 / MORT1-associated CED-3 homolog / MACH / FADD-homologous ...CASP-8 / ICE-like apoptotic protease 5 / MORT1-associated CED-3 homolog / MACH / FADD-homologous ICE/CED-3-like protease / FADD-like ICE / FLICE / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / Caspase-8 subunit p18 / Caspase-8 subunit p10


Mass: 18640.119 Da / Num. of mol.: 1
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: Protein Caspase-8 / Caspase 8 / CASP-8 / ICE-like apoptotic protease 5 / MORT1-associated CED-3 homolog / MACH / FADD-homologous ...CASP-8 / ICE-like apoptotic protease 5 / MORT1-associated CED-3 homolog / MACH / FADD-homologous ICE/CED-3-like protease / FADD-like ICE / FLICE / Apoptotic cysteine protease / Apoptotic protease Mch-5 / CAP4 / Caspase-8 subunit p18 / Caspase-8 subunit p10


Mass: 10901.364 Da / Num. of mol.: 1
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
#3: Chemical ChemComp-B94 / (3S)-3-({[(5S,8R)-2-(3-carboxypropyl)-8-(2-{[(4-chlorophenyl)acetyl]amino}ethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl}amino)-4-oxopentanoic acid


Mass: 591.997 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30ClN5O9
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 146 / Source method: isolated from a natural source / Formula: H2O

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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: 2.62 Å3/Da / Density % sol: 52.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.8
Details: 2 microliters of 100 mM inhibitor stock in DMSO was added to 100 microliters of 8.4 mg/mL protein in 20 mM Tris, 100 mM DTT, pH 8.0. Protein solution was mixed with an equal volume of well ...Details: 2 microliters of 100 mM inhibitor stock in DMSO was added to 100 microliters of 8.4 mg/mL protein in 20 mM Tris, 100 mM DTT, pH 8.0. Protein solution was mixed with an equal volume of well solution (1.0-1.1 M Citrate, 50 mM HEPES or PIPES pH 6.5, 25 mM DTT), VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationMonochromator: Si(111) double-crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→20 Å / Num. all: 29350 / Num. obs: 29346 / % possible obs: 99.6 %
Reflection shellResolution: 1.8→1.85 Å / % possible all: 96.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→19.94 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.936 / SU B: 1.957 / SU ML: 0.063 / Cross valid method: THROUGHOUT / ESU R: 0.117 / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20719 2933 10 %RANDOM
Rwork0.18208 ---
obs0.1846 26415 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 12.497 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20.32 Å20 Å2
2--0.64 Å20 Å2
3----0.96 Å2
Refinement stepCycle: LAST / Resolution: 1.8→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1924 0 48 146 2118
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222036
X-RAY DIFFRACTIONr_bond_other_d0.0010.021366
X-RAY DIFFRACTIONr_angle_refined_deg1.2421.9892757
X-RAY DIFFRACTIONr_angle_other_deg0.8773.0013348
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9665248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.46424.78794
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.75515355
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5121510
X-RAY DIFFRACTIONr_chiral_restr0.0750.2299
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022269
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02384
X-RAY DIFFRACTIONr_nbd_refined0.190.2376
X-RAY DIFFRACTIONr_nbd_other0.1810.21411
X-RAY DIFFRACTIONr_nbtor_refined0.180.2981
X-RAY DIFFRACTIONr_nbtor_other0.0820.2989
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1160.2124
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1620.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2240.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1260.210
X-RAY DIFFRACTIONr_mcbond_it0.7511.51250
X-RAY DIFFRACTIONr_mcbond_other0.1371.5489
X-RAY DIFFRACTIONr_mcangle_it1.20521981
X-RAY DIFFRACTIONr_scbond_it1.9243876
X-RAY DIFFRACTIONr_scangle_it2.9684.5772
LS refinement shellResolution: 1.8→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 198 -
Rwork0.241 1880 -
obs--96.92 %

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