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- PDB-3h11: Zymogen caspase-8:c-FLIPL protease domain complex -

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Basic information

Entry
Database: PDB / ID: 3h11
TitleZymogen caspase-8:c-FLIPL protease domain complex
Components
  • CASP8 and FADD-like apoptosis regulator
  • Caspase-8Caspase 8
  • IETD aldehyde inhibitor
KeywordsAPOPTOSIS / cell death / Caspase / Alternative splicing / Host-virus interaction / Polymorphism / Cytoplasm / Disease mutation / Hydrolase / Phosphoprotein / Protease / Thiol protease / Zymogen
Function / homology
Function and homology information


negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation ...negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / 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 / regulation of necroptotic process / Caspase activation via Death Receptors in the presence of ligand / skeletal muscle tissue regeneration / positive regulation of extracellular matrix organization / positive regulation of glomerular mesangial cell proliferation / positive regulation of macrophage differentiation / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / self proteolysis / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / negative regulation of hepatocyte apoptotic process / natural killer cell activation / negative regulation of necroptotic process / CLEC7A/inflammasome pathway / activation of cysteine-type endopeptidase activity / regulation of tumor necrosis factor-mediated signaling pathway / tumor necrosis factor receptor binding / death receptor binding / positive regulation of hepatocyte proliferation / cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cellular response to transforming growth factor beta stimulus / TNFR1-induced proapoptotic signaling / negative regulation of cardiac muscle cell apoptotic process / execution phase of apoptosis / regulation of innate immune response / RIPK1-mediated regulated necrosis / B cell activation / response to testosterone / pyroptosis / Apoptotic cleavage of cellular proteins / positive regulation of proteolysis / macrophage differentiation / protein maturation / enzyme activator activity / cellular response to organic cyclic compound / extrinsic apoptotic signaling pathway via death domain receptors / cellular response to nitric oxide / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / cysteine-type peptidase activity / skeletal muscle tissue development / negative regulation of canonical NF-kappaB signal transduction / negative regulation of reactive oxygen species biosynthetic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway / keratinocyte differentiation / regulation of cytokine production / cellular response to epidermal growth factor stimulus / T cell activation / cellular response to dexamethasone stimulus / proteolysis involved in protein catabolic process / erythrocyte differentiation / positive regulation of interleukin-1 beta production / Regulation of NF-kappa B signaling / cellular response to estradiol stimulus / apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / Regulation of TNFR1 signaling / NOD1/2 Signaling Pathway / wound healing / positive regulation of neuron projection development / Regulation of necroptotic cell death / neuron differentiation / cellular response to mechanical stimulus / cellular response to insulin stimulus / positive regulation of neuron apoptotic process / response to estradiol / lamellipodium / cell body / positive regulation of NF-kappaB transcription factor activity / heart development / peptidase activity / cellular response to hypoxia / scaffold protein binding / angiogenesis / positive regulation of canonical NF-kappaB signal transduction / response to ethanol / protease binding
Similarity search - Function
Caspase-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / 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 / Death effector domain (DED) profile. / 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
CASP8 and FADD-like apoptosis regulator / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsJeffrey, P.D. / Yu, J.W. / Shi, Y.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: Mechanism of procaspase-8 activation by c-FLIPL.
Authors: Yu, J.W. / Jeffrey, P.D. / Shi, Y.
History
DepositionApr 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 28, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations / Category: database_2 / struct_conn / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CASP8 and FADD-like apoptosis regulator
B: Caspase-8
C: IETD aldehyde inhibitor


Theoretical massNumber of molelcules
Total (without water)62,9833
Polymers62,9833
Non-polymers00
Water2,216123
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4140 Å2
ΔGint-13 kcal/mol
Surface area17360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.990, 76.680, 114.190
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Detailsauthors state that the small peptide (chain C) is a covalent inhibitor, and the native state of the proteins (chain A and chain B) is dimeric.

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Components

#1: Protein CASP8 and FADD-like apoptosis regulator


Mass: 31450.217 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFLAR, CASH, CASP8AP1, CLARP, MRIT / Plasmid: pET21b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: O15519
#2: Protein Caspase-8 / Caspase 8


Mass: 31001.135 Da / Num. of mol.: 1 / Mutation: D359A, D369A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP8, MCH5 / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q14790, caspase-8
#3: Protein/peptide IETD aldehyde inhibitor


Mass: 531.556 Da / Num. of mol.: 1 / Source method: obtained synthetically
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS STATE THAT THIS SEQUENCE DISCREPANCY MAY BE DUE TO VARIATIONS AMONG DIFFERENT CONSTRUCTS IN ...AUTHORS STATE THAT THIS SEQUENCE DISCREPANCY MAY BE DUE TO VARIATIONS AMONG DIFFERENT CONSTRUCTS IN THE DATABASES. RESIDUE 369 IS ASN IN GENBANK ENTRY CAA74366.1

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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: 1.84 Å3/Da / Density % sol: 33.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 10.5
Details: 0.9 M sodium dihydrogen phosphate, 0.8 M dipotassium hydrogen phosphate, 0.1 M N-cyclohexyl-3-aminopropanesulfonic acid (CAPS), 0.2 M lithium sulfate, pH 10.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 31, 2008 / Details: Si(111)
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 1.9→100 Å / Num. all: 37398 / Num. obs: 37398 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 4.7 % / Biso Wilson estimate: 19.6 Å2 / Rsym value: 0.073 / Net I/σ(I): 13.5
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 2.7 / Num. unique all: 3674 / Rsym value: 0.468 / % possible all: 99.7

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Processing

Software
NameVersionClassification
CBASSdata collection
PHASERphasing
CNS1.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→45.8 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1868369.99 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.25 1844 4.9 %RANDOM
Rwork0.212 ---
obs0.212 37271 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.9415 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso mean: 37.4 Å2
Baniso -1Baniso -2Baniso -3
1-4.37 Å20 Å20 Å2
2--8.77 Å20 Å2
3----13.14 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 1.9→45.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3595 0 0 123 3718
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.95
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.341 290 4.7 %
Rwork0.289 5830 -
obs--99.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5modifiers.param

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