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- PDB-8eg5: huCaspase-6 in complex with inhibitor 3a -

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Basic information

Entry
Database: PDB / ID: 8eg5
TitlehuCaspase-6 in complex with inhibitor 3a
Components
  • Caspase-6 subunit p11
  • Caspase-6 subunit p18
KeywordsAPOPTOSIS / HYDROLASE/INHIBITOR / cysteine covalent inhibitor competitive inhibitor protease / PROTEASE-PROTEASE INHIBITOR complex / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


caspase-6 / Breakdown of the nuclear lamina / regulation of programmed cell death / positive regulation of necroptotic process / cellular response to staurosporine / : / : / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptotic inflammatory response / hepatocyte apoptotic process ...caspase-6 / Breakdown of the nuclear lamina / regulation of programmed cell death / positive regulation of necroptotic process / cellular response to staurosporine / : / : / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptotic inflammatory response / hepatocyte apoptotic process / Apoptotic cleavage of cellular proteins / protein autoprocessing / intrinsic apoptotic signaling pathway by p53 class mediator / Caspase-mediated cleavage of cytoskeletal proteins / activation of innate immune response / cysteine-type peptidase activity / epithelial cell differentiation / positive regulation of neuron apoptotic process / positive regulation of apoptotic process / cysteine-type endopeptidase activity / apoptotic process / proteolysis / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
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. ...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
Similarity search - Domain/homology
Chem-UCI / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 Å
AuthorsZhao, Y. / Fan, P. / Liu, J. / Wang, Y. / Van Horn, K. / Wang, D. / Medina-Cleghorn, D. / Lee, P. / Bryant, C. / Altobelli, C. ...Zhao, Y. / Fan, P. / Liu, J. / Wang, Y. / Van Horn, K. / Wang, D. / Medina-Cleghorn, D. / Lee, P. / Bryant, C. / Altobelli, C. / Jaishankar, P. / Ng, R.A. / Ambrose, A.J. / Tang, Y. / Arkin, M.R. / Renslo, A.R.
Funding support United States, 2items
OrganizationGrant numberCountry
CHDI FoundationA-1260 United States
Other privateAlzheimer's Association DVT-14-322219
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.
Authors: Van Horn, K.S. / Wang, D. / Medina-Cleghorn, D. / Lee, P.S. / Bryant, C. / Altobelli, C. / Jaishankar, P. / Leung, K.K. / Ng, R.A. / Ambrose, A.J. / Tang, Y. / Arkin, M.R. / Renslo, A.R.
History
DepositionSep 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-6 subunit p18
B: Caspase-6 subunit p11
C: Caspase-6 subunit p18
D: Caspase-6 subunit p11
E: Caspase-6 subunit p18
F: Caspase-6 subunit p11
G: Caspase-6 subunit p18
H: Caspase-6 subunit p11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,22915
Polymers119,2178
Non-polymers2,0127
Water12,791710
1
A: Caspase-6 subunit p18
B: Caspase-6 subunit p11
C: Caspase-6 subunit p18
D: Caspase-6 subunit p11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5847
Polymers59,6094
Non-polymers9753
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14870 Å2
ΔGint-92 kcal/mol
Surface area20200 Å2
MethodPISA
2
E: Caspase-6 subunit p18
F: Caspase-6 subunit p11
G: Caspase-6 subunit p18
H: Caspase-6 subunit p11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6468
Polymers59,6094
Non-polymers1,0374
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15180 Å2
ΔGint-92 kcal/mol
Surface area20210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.770, 60.880, 101.260
Angle α, β, γ (deg.)90.000, 91.410, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Caspase-6 subunit p18 / Caspase-6 subunit p20


Mass: 17301.891 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP6, MCH2 / Production host: Escherichia coli (E. coli) / References: UniProt: P55212
#2: Protein
Caspase-6 subunit p11 / Caspase-6 subunit p10


Mass: 12502.361 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP6, MCH2 / Production host: Escherichia coli (E. coli) / References: UniProt: P55212
#3: Chemical
ChemComp-UCI / (3R,5S)-1-(ethanesulfonyl)-5-phenyl-N-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxamide (bound form)


Mass: 456.479 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H23F3N2O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 710 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.19 Å3/Da / Density % sol: 43.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1 M TRIS pH 8.5; 12% w/v PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.14→49.49 Å / Num. obs: 57282 / % possible obs: 99.9 % / Redundancy: 6.8 % / CC1/2: 0.996 / Rmerge(I) obs: 0.149 / Rpim(I) all: 0.062 / Rrim(I) all: 0.161 / Net I/σ(I): 10.2
Reflection shell

Diffraction-ID: 1 / Redundancy: 6.7 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.14-2.20.9322974844380.6880.3881.0112.2100
9.33-49.440.03649987430.9990.0150.03936.998.8

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Processing

Software
NameVersionClassification
Aimless0.7.7data scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P4U

3p4u


Resolution: 2.14→49.49 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.89 / SU B: 7.671 / SU ML: 0.196 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.316 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2629 2887 5 %RANDOM
Rwork0.2148 ---
obs0.2172 54362 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 108.58 Å2 / Biso mean: 31.279 Å2 / Biso min: 6.03 Å2
Baniso -1Baniso -2Baniso -3
1--0.9 Å20 Å2-0.03 Å2
2---1.66 Å2-0 Å2
3---2.56 Å2
Refinement stepCycle: final / Resolution: 2.14→49.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7819 0 136 721 8676
Biso mean--53.55 37.18 -
Num. residues----970
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0138283
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177649
X-RAY DIFFRACTIONr_angle_refined_deg1.3371.64611203
X-RAY DIFFRACTIONr_angle_other_deg1.1861.58117753
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1351004
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.51721.25448
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.072151441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1761559
X-RAY DIFFRACTIONr_chiral_restr0.0560.21046
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.029177
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021904
LS refinement shellResolution: 2.14→2.196 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 208 -
Rwork0.292 4012 -
all-4220 -
obs--99.95 %

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