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- PDB-4nbl: Tailoring Small Molecules for an Allosteric Site on Procaspase-6 -

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Basic information

Entry
Database: PDB / ID: 4nbl
TitleTailoring Small Molecules for an Allosteric Site on Procaspase-6
ComponentsCaspase-6
Keywordshydrolase/hydrolase inhibitor / procaspse-6 / caspase-6 zymogen / allosteric / Structure Based Drug Design / Caspase / cysteine protease / hydrolase-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
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 ...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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-2J6 / PHOSPHATE ION / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.756 Å
AuthorsMurray, J.M. / Steffek, M.
CitationJournal: Chemmedchem / Year: 2014
Title: Tailoring small molecules for an allosteric site on procaspase-6.
Authors: Murray, J. / Giannetti, A.M. / Steffek, M. / Gibbons, P. / Hearn, B.R. / Cohen, F. / Tam, C. / Pozniak, C. / Bravo, B. / Lewcock, J. / Jaishankar, P. / Ly, C.Q. / Zhao, X. / Tang, Y. / ...Authors: Murray, J. / Giannetti, A.M. / Steffek, M. / Gibbons, P. / Hearn, B.R. / Cohen, F. / Tam, C. / Pozniak, C. / Bravo, B. / Lewcock, J. / Jaishankar, P. / Ly, C.Q. / Zhao, X. / Tang, Y. / Chugha, P. / Arkin, M.R. / Flygare, J. / Renslo, A.R.
History
DepositionOct 23, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-6
B: Caspase-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4949
Polymers64,6282
Non-polymers8667
Water6,161342
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4760 Å2
ΔGint-57 kcal/mol
Surface area21060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.784, 115.784, 79.544
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-563-

HOH

21B-560-

HOH

31B-578-

HOH

41B-646-

HOH

51B-668-

HOH

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Components

#1: Protein Caspase-6 / CASP-6 / Apoptotic protease Mch-2 / Caspase-6 subunit p18 / Caspase-6 subunit p11


Mass: 32313.857 Da / Num. of mol.: 2 / Mutation: C163A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP6, MCH2, procaspase-6 / Plasmid: pet / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P55212, caspase-6
#2: Chemical ChemComp-2J6 / 5-fluoro-2-({[3-(pyrimidin-2-yl)pyridin-2-yl]amino}methyl)phenol


Mass: 296.299 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13FN4O
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 342 / Source method: isolated from a natural source / Formula: H2O

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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: 2.06 Å3/Da / Density % sol: 40.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 2-Methyl-2,4-pentanediol, 0.3 M Ammonium Phosphate monobasic, 0.1 M Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 20, 2010
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.756→115.77 Å / Num. all: 54169 / Num. obs: 54169 / % possible obs: 99.6 % / Redundancy: 9.2 % / Biso Wilson estimate: 19.53 Å2 / Rsym value: 0.066 / Net I/σ(I): 21
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
1.76-1.858.60.5111.50.511199
1.85-1.968.90.322.40.32199.5
1.96-2.19.20.2023.80.202199.4
2.1-2.279.40.1325.80.132199.7
2.27-2.489.50.0977.80.097199.7
2.48-2.789.50.07410.10.074199.8
2.78-3.219.40.05312.90.053199.9
3.21-3.939.10.0415.50.041100
3.93-5.559.40.03418.50.0341100
5.55-115.778.80.03118.70.0311100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASERphasing
PHENIXdev_1565refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.756→65.563 Å / Occupancy max: 1 / Occupancy min: 0.44 / SU ML: 0.15 / σ(F): 1.35 / Phase error: 15.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.179 2768 5.12 %
Rwork0.1551 --
obs0.1563 54113 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.9218 Å2
Refinement stepCycle: LAST / Resolution: 1.756→65.563 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4006 0 52 342 4400
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074191
X-RAY DIFFRACTIONf_angle_d1.0695656
X-RAY DIFFRACTIONf_dihedral_angle_d12.7991513
X-RAY DIFFRACTIONf_chiral_restr0.048598
X-RAY DIFFRACTIONf_plane_restr0.006717
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7554-1.78570.23531060.20532500X-RAY DIFFRACTION97
1.7857-1.81810.22531210.18782506X-RAY DIFFRACTION99
1.8181-1.85310.21131350.1882530X-RAY DIFFRACTION99
1.8531-1.89090.23551610.17342500X-RAY DIFFRACTION99
1.8909-1.93210.21151370.16112527X-RAY DIFFRACTION99
1.9321-1.9770.18941400.15962534X-RAY DIFFRACTION99
1.977-2.02640.21360.15492527X-RAY DIFFRACTION99
2.0264-2.08120.20721450.15482523X-RAY DIFFRACTION99
2.0812-2.14250.1651510.14932529X-RAY DIFFRACTION99
2.1425-2.21160.18161260.14282552X-RAY DIFFRACTION99
2.2116-2.29070.1741390.14842548X-RAY DIFFRACTION100
2.2907-2.38240.21131360.15552551X-RAY DIFFRACTION100
2.3824-2.49080.18771560.15442555X-RAY DIFFRACTION100
2.4908-2.62220.20531310.16592583X-RAY DIFFRACTION100
2.6222-2.78650.19831350.16452580X-RAY DIFFRACTION100
2.7865-3.00160.16021600.15362574X-RAY DIFFRACTION100
3.0016-3.30370.17691470.15232607X-RAY DIFFRACTION100
3.3037-3.78170.16381410.1382615X-RAY DIFFRACTION100
3.7817-4.76430.12991350.13062677X-RAY DIFFRACTION100
4.7643-65.60850.18011300.17712827X-RAY DIFFRACTION100
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)
11.5713-0.3039-0.29521.80940.26831.57320.00110.03320.0015-0.0716-0.04240.1476-0.025-0.10720.03150.10180.0049-0.03290.1067-0.01030.094217.548623.2348-19.3649
21.79590.12490.20151.8425-0.00231.7336-0.05590.06530.0108-0.07750.0418-0.2424-0.05090.22470.02730.0621-0.00050.01330.16510.00650.130944.245326.419-14.7181
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A
2X-RAY DIFFRACTION2chain B

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