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- PDB-8eg6: huCaspase-6 in complex with inhibitor 2a -

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Basic information

Entry
Database: PDB / ID: 8eg6
TitlehuCaspase-6 in complex with inhibitor 2a
Components(Caspase-6 subunit ...) x 2
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
DI(HYDROXYETHYL)ETHER / Chem-US9 / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 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 23, 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)121,70529
Polymers119,2178
Non-polymers2,48821
Water16,574920
1
A: Caspase-6 subunit p18
B: Caspase-6 subunit p11
E: Caspase-6 subunit p18
F: Caspase-6 subunit p11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,99017
Polymers59,6094
Non-polymers1,38113
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16430 Å2
ΔGint-129 kcal/mol
Surface area19940 Å2
MethodPISA
2
C: Caspase-6 subunit p18
D: Caspase-6 subunit p11
G: Caspase-6 subunit p18
H: Caspase-6 subunit p11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,71512
Polymers59,6094
Non-polymers1,1078
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15460 Å2
ΔGint-93 kcal/mol
Surface area20530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.580, 60.730, 101.700
Angle α, β, γ (deg.)90.000, 91.040, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12A
22E
13A
23G
14B
24D
15B
25F
16B
26H
17C
27E
18C
28G
19D
29F
110D
210H
111E
211G
112F
212H

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PHEPHEILEILEAA31 - 1732 - 144
21PHEPHEILEILECC31 - 1732 - 144
12PHEPHELEULEUAA31 - 1752 - 146
22PHEPHELEULEUEE31 - 1752 - 146
13PHEPHELEULEUAA31 - 1752 - 146
23PHEPHELEULEUGG31 - 1752 - 146
14SERSERSERSERBB196 - 2924 - 100
24SERSERSERSERDD196 - 2924 - 100
15VALVALPROPROBB197 - 2905 - 98
25VALVALPROPROFF197 - 2905 - 98
16SERSERSERSERBB196 - 2924 - 100
26SERSERSERSERHH196 - 2924 - 100
17PHEPHEILEILECC31 - 1732 - 144
27PHEPHEILEILEEE31 - 1732 - 144
18PHEPHEILEILECC31 - 1732 - 144
28PHEPHEILEILEGG31 - 1732 - 144
19VALVALPROPRODD197 - 2905 - 98
29VALVALPROPROFF197 - 2905 - 98
110SERSERSERSERDD196 - 2924 - 100
210SERSERSERSERHH196 - 2924 - 100
111METMETASPASPEE30 - 1761 - 147
211METMETASPASPGG30 - 1761 - 147
112VALVALPROPROFF197 - 2905 - 98
212VALVALPROPROHH197 - 2905 - 98

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12

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Components

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Caspase-6 subunit ... , 2 types, 8 molecules ACEGBDFH

#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

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Non-polymers , 5 types, 941 molecules

#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-US9 / (3R)-1-(ethanesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxamide


Mass: 380.383 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H19F3N2O4S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 920 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 43.85 %
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: 1.82→49.38 Å / Num. obs: 92718 / % possible obs: 100 % / Redundancy: 6.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.041 / Rrim(I) all: 0.108 / Net I/σ(I): 12.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.82-1.8570.9513197945920.7680.3841.0272.1100
9.97-49.336.40.03638856110.9990.0150.0394099.1

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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: 1.82→49.38 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.95 / SU B: 2.883 / SU ML: 0.087 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.128 / ESU R Free: 0.119 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2006 4599 5 %RANDOM
Rwork0.165 ---
obs0.1668 88108 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 125.11 Å2 / Biso mean: 26.512 Å2 / Biso min: 12.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.73 Å2-0 Å20.34 Å2
2---1.18 Å2-0 Å2
3---1.9 Å2
Refinement stepCycle: final / Resolution: 1.82→49.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7827 0 156 930 8913
Biso mean--38.17 38.75 -
Num. residues----971
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0138340
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177751
X-RAY DIFFRACTIONr_angle_refined_deg1.5431.64811272
X-RAY DIFFRACTIONr_angle_other_deg1.3811.58117999
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.15251022
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.11121.178450
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.094151458
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0511560
X-RAY DIFFRACTIONr_chiral_restr0.0790.21052
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029220
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021900
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A45170.08
12C45170.08
21A45880.08
22E45880.08
31A45210.09
32G45210.09
41B29390.08
42D29390.08
51B28920.08
52F28920.08
61B29430.08
62H29430.08
71C44880.08
72E44880.08
81C44190.09
82G44190.09
91D28690.08
92F28690.08
101D29280.06
102H29280.06
111E45530.08
112G45530.08
121F28820.07
122H28820.07
LS refinement shellResolution: 1.82→1.867 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 306 -
Rwork0.253 6469 -
all-6775 -
obs--99.91 %

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