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- PDB-2c2z: Crystal structure of caspase-8 in complex with aza-peptide Michae... -

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Basic information

Entry
Database: PDB / ID: 2c2z
TitleCrystal structure of caspase-8 in complex with aza-peptide Michael acceptor inhibitor
Components
  • AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID
  • CASPASE-8 P10 SUBUNIT
  • CASPASE-8 P18 SUBUNIT
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / APOPTOSIS / CYSTEINE-PROTEASE / ICE / THIOL PROTEASE / ZYMOGEN / CPP32 / YAMA / AZA-PEPTIDE / MICHAEL ACCEPTOR / AZA-ASP / CLAN CD
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 / TRAIL-activated apoptotic signaling pathway / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase ...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 / TRAIL-activated apoptotic signaling pathway / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / Activation, myristolyation of BID and translocation to mitochondria / 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 / CLEC7A/inflammasome pathway / natural killer cell activation / negative regulation of necroptotic process / activation of cysteine-type endopeptidase activity / regulation of tumor necrosis factor-mediated signaling pathway / 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 / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / 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 / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / cysteine-type peptidase activity / 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 / peptidase activity / heart development / cell body / scaffold protein binding / angiogenesis / positive regulation of canonical NF-kappaB signal transduction / response to ethanol / 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 / cytoplasm / cytosol
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
Cbz-Leu-Glu-Thr-AAsp-CHCH-CON-tetrahydroquinoline / DITHIANE DIOL / Caspase-8
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.95 Å
AuthorsGanesan, R. / Jelakovic, S. / Ekici, O.D. / Li, Z.Z. / James, K.E. / Asgian, J.L. / Campbell, A.J. / Mikolajczyk, J. / Salvesen, G.S. / Powers, J.C. / Gruetter, M.G.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Selective and Potent Inhibitors of Caspases-2, -3, -6, -7, -8, -9, and - 10.
Authors: Ekici, O.D. / Li, Z.Z. / Campbell, A.J. / James, K.E. / Asgian, J.L. / Mikolajczyk, J. / Salvesen, G.S. / Ganesan, R. / Jelakovic, S. / Grutter, M.G. / Powers, J.C.
History
DepositionOct 2, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2006Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Jul 20, 2011Group: Other / Structure summary
Revision 1.3Nov 30, 2012Group: Other
Revision 1.4Feb 8, 2017Group: Source and taxonomy

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CASPASE-8 P18 SUBUNIT
B: CASPASE-8 P10 SUBUNIT
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,2204
Polymers31,0683
Non-polymers1521
Water5,837324
1
A: CASPASE-8 P18 SUBUNIT
B: CASPASE-8 P10 SUBUNIT
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID
hetero molecules

A: CASPASE-8 P18 SUBUNIT
B: CASPASE-8 P10 SUBUNIT
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,4408
Polymers62,1356
Non-polymers3042
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+1/31
MethodPQS
Unit cell
Length a, b, c (Å)62.520, 62.520, 129.940
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 P18 SUBUNIT


Mass: 18027.570 Da / Num. of mol.: 1 / Fragment: ALPHA SUB-UNIT, RESIDUES 218-374
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET11D / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q14790, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein CASPASE-8 P10 SUBUNIT


Mass: 12238.839 Da / Num. of mol.: 1 / Fragment: BETA-SUBUNIT, RESIDUES 376-479
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET11D / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q14790, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL) -14-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL] -11-[(1R)-1-HYDROXYETHYL]-5-(2-METHYLPROPYL)-3,6,9,12-TETRAOXO -1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID


Type: Peptide-like / Class: Inhibitor / Mass: 801.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
References: Cbz-Leu-Glu-Thr-AAsp-CHCH-CON-tetrahydroquinoline
#4: Chemical ChemComp-DTD / DITHIANE DIOL


Mass: 152.235 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2S2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 324 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE INITIAL LIGAND USED IN THE EXPERIMENT WAS CBZ-LETAD-CH=CH-CO- TETRAHYDROQUINOLINE. UPON ...THE INITIAL LIGAND USED IN THE EXPERIMENT WAS CBZ-LETAD-CH=CH-CO- TETRAHYDROQUINOLINE. UPON REACTION, THE DOUBLE BOND OPENED UP AND FORMED A COVALENT BOND BETWEEN ATOM C10 OF RESIDUE MX5 5 OF CHAIN C AND ATOM SG OF CYS 360 OF CHAIN A.

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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: 2.36 Å3/Da / Density % sol: 48 %
Crystal growpH: 8 / Details: 1.4M SODIUM CITRATE, 100MM HEPES PH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.90001
DetectorType: MARRESEARCH / Detector: CCD / Date: Apr 21, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.90001 Å / Relative weight: 1
ReflectionResolution: 1.92→20 Å / Num. obs: 22937 / % possible obs: 98.9 % / Observed criterion σ(I): 0 / Redundancy: 7.8 % / Biso Wilson estimate: 8 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 29.61
Reflection shellResolution: 1.92→2.02 Å / Redundancy: 7.55 % / Rmerge(I) obs: 0.09 / Mean I/σ(I) obs: 20.38 / % possible all: 99.6

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Processing

Software
NameVersionClassification
CNS1.1refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 1.95→10 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 2150768.42 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: MISSING RESIDUES A216-222, A372-374, B374-389
RfactorNum. reflection% reflectionSelection details
Rfree0.187 648 3 %RANDOM
Rwork0.171 ---
obs0.171 21815 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 63.5 Å2 / ksol: 0.45 e/Å3
Displacement parametersBiso mean: 19.5 Å2
Baniso -1Baniso -2Baniso -3
1-2.75 Å2-0.09 Å20 Å2
2--2.75 Å20 Å2
3----5.5 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.2 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.07 Å0.07 Å
Refinement stepCycle: LAST / Resolution: 1.95→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1968 0 8 324 2300
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
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_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.83
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: 1.95→2.07 Å / Rfactor Rfree error: 0.019 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.198 104 2.9 %
Rwork0.18 3473 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3DTD.PARDTD.TOP

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