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- PDB-6x8h: Caspase-8 in complex with AOMK inhibitor, Ac-DW3-KE, forms tetrah... -

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Basic information

Entry
Database: PDB / ID: 6x8h
TitleCaspase-8 in complex with AOMK inhibitor, Ac-DW3-KE, forms tetrahedral adduct
Components
  • (Caspase-8) x 2
  • Ac-DW3-KE
KeywordsHYDROLASE/HYDROLASE INHIBITOR / inhibitor / tetrahedral / complex / 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 / 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 / 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-8 / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / 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
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsSolania, A. / Xu, J.H. / Wolan, D.W.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5R21AI112796 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM118382 United States
CitationJournal: To Be Published
Title: Caspase-8 in complex with AOMK inhibitor, Ac-DW3-KE, forms tetrahedral adduct
Authors: Solania, A. / Xu, J.H. / Wolan, D.W.
History
DepositionJun 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Advisory / Author supporting evidence / Database references
Category: database_2 / pdbx_audit_support / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _pdbx_validate_torsion.phi / _pdbx_validate_torsion.psi / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_label_atom_id

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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: Ac-DW3-KE


Theoretical massNumber of molelcules
Total (without water)30,8873
Polymers30,8873
Non-polymers00
Water3,801211
1
A: Caspase-8
B: Caspase-8
C: Ac-DW3-KE

A: Caspase-8
B: Caspase-8
C: Ac-DW3-KE


Theoretical massNumber of molelcules
Total (without water)61,7746
Polymers61,7746
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_645y+1,x-1,-z1
Buried area16490 Å2
ΔGint-106 kcal/mol
Surface area18290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.498, 62.498, 129.360
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11B-550-

HOH

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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: 19148.680 Da / Num. of mol.: 1 / Fragment: p18 (UNP residues 276-443)
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 / 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: 10901.364 Da / Num. of mol.: 1 / Fragment: p10 (UNP residues 444-538)
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: Protein/peptide Ac-DW3-KE


Mass: 836.952 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 47.91 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.1 / Details: 1:1 protein : 0.10 M HEPES, 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 PILATUS3 6M / Detector: PIXEL / Date: Apr 18, 2017
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: 1.48→50 Å / Num. obs: 49543 / % possible obs: 99.8 % / Redundancy: 13.3 % / Biso Wilson estimate: 9.13 Å2 / CC1/2: 0.97 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.036 / Rrim(I) all: 0.133 / Net I/σ(I): 0.22
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.48-1.5170.68423820.7990.2750.740.79898.5
1.51-1.538.40.59524300.8910.2160.6350.81199.5
1.53-1.56100.55424770.9150.1830.5840.79199.8
1.56-1.5912.40.52624270.9550.1540.5490.77499.9
1.59-1.6314.70.49524030.9670.1320.5120.77100
1.63-1.6714.80.43324660.9740.1150.4490.781100
1.67-1.7114.60.38624490.9760.1040.40.77999.9
1.71-1.7514.30.33624530.9840.0910.3480.78499.9
1.75-1.8113.40.29824540.9830.0840.310.789100
1.81-1.8614.20.25324420.9880.0690.2620.802100
1.86-1.9314.90.2224810.9920.0580.2270.821100
1.93-2.0114.70.18224730.9930.0490.1890.875100
2.01-2.114.30.14924550.9950.0410.1550.907100
2.1-2.2113.20.12524980.9960.0360.130.97199.8
2.21-2.35150.11224710.9970.030.1160.997100
2.35-2.5314.80.10424820.9970.0280.1080.924100
2.53-2.7913.80.09725000.9970.0270.1010.97100
2.79-3.1914.50.08125500.9980.0220.0841.078100
3.19-4.02140.06625450.9980.0180.0681.17699.8
4.02-5013.40.06827050.9970.0190.0711.3499.8

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4JJ7

4jj7


Resolution: 1.48→49.931 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 14.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1672 2403 4.86 %
Rwork0.1489 47091 -
obs0.1498 49494 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.49 Å2 / Biso mean: 14.4543 Å2 / Biso min: 4.14 Å2
Refinement stepCycle: final / Resolution: 1.48→49.931 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1968 0 60 211 2239
Biso mean--14.55 25.76 -
Num. residues----241
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.4803-1.51050.22271360.1886269299
1.5105-1.54340.15881300.1643271799
1.5434-1.57930.19141480.16072721100
1.5793-1.61880.18621120.15152749100
1.6188-1.66260.17251610.1492711100
1.6626-1.71150.15781500.1492733100
1.7115-1.76670.1511290.14492765100
1.7667-1.82990.18071400.14962757100
1.8299-1.90310.18221360.14312749100
1.9031-1.98980.15891420.14372749100
1.9898-2.09470.15661820.1382735100
2.0947-2.22590.18571160.13632797100
2.2259-2.39780.15671610.14092779100
2.3978-2.63910.15311310.15382777100
2.6391-3.02090.16921370.15012824100
3.0209-3.80580.15681300.13872856100
3.8058-49.9310.16961620.16112980100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.5668-0.0376-0.38261.641-0.75852.080.02220.09330.11350.02540.10470.1434-0.0024-0.2277-0.08380.03380.0007-0.03090.0542-0.01820.056433.3005-14.23993.7843
21.11230.6635-0.00410.65840.231.60390.02560.04590.00730.0353-0.01350.04460.0801-0.1019-0.00520.04880.03040.00480.058-0.00820.069829.4311-17.05467.9315
30.56010.7786-0.44092.4143-1.62022.6321-0.01130.05150.0118-0.07810.0480.08620.1071-0.1281-0.03930.02580.0086-0.01040.0714-0.01180.072132.7076-20.91310.5712
41.0961-0.62121.05030.7906-0.9412.3116-0.0269-0.0087-0.01740.04880.0126-0.01270.002-0.0533-0.01590.05340.00730.00480.026-0.01840.049143.5119-21.51654.6031
50.69430.0671-0.92670.3237-0.0734.73380.01310.0045-0.0078-0.00730.01130.0168-0.0772-0.0826-0.0440.01650.0005-0.00960.0371-0.00570.063341.8957-20.94353.7059
61.8472-0.1528-0.20312.6497-0.9272.0529-0.0015-0.09870.07430.1479-0.0124-0.0693-0.1190.10410.02310.0478-0.0049-0.01020.0581-0.01710.040848.6926-14.850913.4255
72.3759-0.3544-0.28274.04020.20232.5223-0.0186-0.02130.14130.07980.01090.0175-0.0982-0.05010.00810.02740.0118-0.00770.0597-0.010.044747.557-12.7325-2.6352
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 223 through 250 )A223 - 250
2X-RAY DIFFRACTION2chain 'A' and (resid 251 through 301 )A251 - 301
3X-RAY DIFFRACTION3chain 'A' and (resid 302 through 340 )A302 - 340
4X-RAY DIFFRACTION4chain 'A' and (resid 341 through 374 )A341 - 374
5X-RAY DIFFRACTION5chain 'B' and (resid 390 through 419 )B390 - 419
6X-RAY DIFFRACTION6chain 'B' and (resid 420 through 464 )B420 - 464
7X-RAY DIFFRACTION7chain 'B' and (resid 465 through 478 )B465 - 478

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