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- PDB-1qdu: CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE... -

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Basic information

Entry
Database: PDB / ID: 1qdu
TitleCRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR ZEVD-DCBMK
Components
  • CASPASE-8 ALPHA-CHAIN
  • CASPASE-8 BETA-CHAIN
  • PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
KeywordsHYDROLASE/HYDROLASE INHIBITOR / APOPTOSIS / CYSTEINE PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
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 / 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 / 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 / cysteine-type endopeptidase activity involved in apoptotic process / TNFR1-induced proapoptotic signaling / execution phase of apoptosis / regulation of innate immune response / RIPK1-mediated regulated necrosis / B cell activation / pyroptosis / 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 / 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 / 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
GLU-VAL-DEHYDROXYMETHYLASPARTIC ACID INHIBITOR / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsBlanchard, H. / Grutter, M.G.
CitationJournal: Structure Fold.Des. / Year: 1999
Title: The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.
Authors: Blanchard, H. / Kodandapani, L. / Mittl, P.R. / Marco, S.D. / Krebs, J.F. / Wu, J.C. / Tomaselli, K.J. / Grutter, M.G.
History
DepositionJul 10, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 4, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.classification / _software.name
Revision 1.5Apr 3, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / 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_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CASPASE-8 ALPHA-CHAIN
B: CASPASE-8 BETA-CHAIN
T: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
C: CASPASE-8 ALPHA-CHAIN
D: CASPASE-8 BETA-CHAIN
U: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
E: CASPASE-8 ALPHA-CHAIN
F: CASPASE-8 BETA-CHAIN
V: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
G: CASPASE-8 ALPHA-CHAIN
H: CASPASE-8 BETA-CHAIN
W: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
I: CASPASE-8 ALPHA-CHAIN
J: CASPASE-8 BETA-CHAIN
X: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
K: CASPASE-8 ALPHA-CHAIN
L: CASPASE-8 BETA-CHAIN
Y: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)168,90018
Polymers168,90018
Non-polymers00
Water2,630146
1
A: CASPASE-8 ALPHA-CHAIN
B: CASPASE-8 BETA-CHAIN
T: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
C: CASPASE-8 ALPHA-CHAIN
D: CASPASE-8 BETA-CHAIN
U: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)56,3006
Polymers56,3006
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16150 Å2
ΔGint-80 kcal/mol
Surface area18740 Å2
MethodPISA
2
E: CASPASE-8 ALPHA-CHAIN
F: CASPASE-8 BETA-CHAIN
V: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
G: CASPASE-8 ALPHA-CHAIN
H: CASPASE-8 BETA-CHAIN
W: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)56,3006
Polymers56,3006
Non-polymers00
Water905
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16110 Å2
ΔGint-80 kcal/mol
Surface area18720 Å2
MethodPISA
3
I: CASPASE-8 ALPHA-CHAIN
J: CASPASE-8 BETA-CHAIN
X: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR
K: CASPASE-8 ALPHA-CHAIN
L: CASPASE-8 BETA-CHAIN
Y: PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR


Theoretical massNumber of molelcules
Total (without water)56,3006
Polymers56,3006
Non-polymers00
Water905
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16170 Å2
ΔGint-80 kcal/mol
Surface area18600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.900, 206.530, 102.050
Angle α, β, γ (deg.)90.00, 102.30, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
CASPASE-8 ALPHA-CHAIN


Mass: 17416.957 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PET21B / Production host: Escherichia coli (E. coli)
References: UniProt: Q14790, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein
CASPASE-8 BETA-CHAIN


Mass: 10186.642 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PET21B / Production host: Escherichia coli (E. coli)
References: UniProt: Q14790, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide
PHQ-GLU-VAL-ASP-DICHLOROMETHYLKETONE INHIBITOR / Z-EVD-DCBMK


Type: Peptide-like / Class: Inhibitor / Mass: 546.398 Da / Num. of mol.: 6 / Source method: obtained synthetically / Details: THE PEPTIDE WAS CHEMICALLY SYNTHESIZED. / References: GLU-VAL-DEHYDROXYMETHYLASPARTIC ACID INHIBITOR
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 146 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE UNBOUND INHIBITOR (CHAINS T,U,V,W,X,Y) IS CARBOBENZOXY-GLU-VAL-ASP-DICHLOROMETHYLKETONE. UPON ...THE UNBOUND INHIBITOR (CHAINS T,U,V,W,X,Y) IS CARBOBENZOXY-GLU-VAL-ASP-DICHLOROMETHYLKETONE. UPON REACTION WITH THE ENZYME CHLORINE DISSOCIATES AND THE INHIBITOR COVALENTLY BINDS TO THE SG CYS 285 OF THE ENZYME.
Sequence detailsAMINO ACID RESIDUES ARE NUMBERED TO FACILITATE COMPARISON WITH CASPASE-1 (INTERLEUKIN 1-BETA ...AMINO ACID RESIDUES ARE NUMBERED TO FACILITATE COMPARISON WITH CASPASE-1 (INTERLEUKIN 1-BETA CONVERTING ENZYME PDB ENTRY 1ICE). RESIDUES IN CASPASE-8 ARE ASSIGNED THE NUMBERS OF THE HOMOLOGOUS RESIDUES IN THE ALIGNED THREE-DIMENSIONAL STRUCTURE OF CASPASE-1. CASPASE-8 SEQUENCE NUMBERS ARE OMITTED WHEN NO CASPASE-1-RELATED RESIDUE IS PRESENT IN CASPASE-8, AND CASPASE-8-SPECIFIC INSERTIONS ARE INDICATED BY THE ADDITION OF LETTERS TO THE CASPASE-1 SEQUENCE NUMBERS.

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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: 2.86 Å3/Da / Density % sol: 57.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.3
Details: 300mM ammonium phosphate, 27% (w/v) isopropanol, 100mM sodium phosphate, pH 6.3, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃ / Method: vapor diffusion
Details: drop consists of equal volume of protein and reservoir solutions
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
12-4 mg/mlprotein1drop
2300 mMammonium phosphate1reservoir
327 %(w/v)isopropanol1reservoir
4100 mMsodium phosphate1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM1A / Wavelength: 0.873
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Oct 2, 1997
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2.8→100 Å / Num. all: 44902 / Num. obs: 44902 / % possible obs: 96.3 % / Observed criterion σ(I): 2 / Redundancy: 3.4 % / Rmerge(I) obs: 0.084 / Net I/σ(I): 17.1
Reflection shellResolution: 2.8→2.85 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.469 / Mean I/σ(I) obs: 2.1 / Num. unique all: 2041 / % possible all: 84.7
Reflection shell
*PLUS
% possible obs: 84.7 % / Num. unique obs: 2041

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Processing

Software
NameVersionClassification
AMoREphasing
X-PLOR3.851refinement
XDSdata reduction
AUTOMARdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: HOMOLOGY MODEL

Resolution: 2.8→100 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.302 4003 10.1 %RANDOM
Rwork0.23 ---
all-44902 --
obs-39559 97 %-
Refinement stepCycle: LAST / Resolution: 2.8→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11802 0 0 146 11948
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.01
X-RAY DIFFRACTIONx_angle_deg1.5
X-RAY DIFFRACTIONx_dihedral_angle_d26.8
X-RAY DIFFRACTIONx_improper_angle_d0.7
Software
*PLUS
Name: X-PLOR / Version: 3.851 / Classification: refinement
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg26.8
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.7

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