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

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Basic information

Entry
Database: PDB / ID: 4nbk
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 / 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 / hepatocyte apoptotic process / Apoptotic cleavage of cellular proteins ...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 / hepatocyte apoptotic process / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / intrinsic apoptotic signaling pathway by p53 class mediator / protein autoprocessing / Caspase-mediated cleavage of cytoskeletal proteins / cysteine-type peptidase activity / epithelial cell differentiation / activation of innate immune response / 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
2-{[(3-methylpyridin-2-yl)amino]methyl}phenol / PHOSPHATE ION / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.936 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)65,4129
Polymers64,6282
Non-polymers7847
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4710 Å2
ΔGint-56 kcal/mol
Surface area20510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.700, 115.700, 79.691
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-619-

HOH

21A-629-

HOH

31B-578-

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 / Fragment: unp residues 24-293 / 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-2J5 / 2-{[(3-methylpyridin-2-yl)amino]methyl}phenol


Mass: 214.263 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14N2O
#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.: 320 / 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: 40.39 %
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: Jan 26, 2010
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.936→115.742 Å / Num. all: 40739 / Num. obs: 40739 / % possible obs: 100 % / Redundancy: 7.1 % / Rsym value: 0.084 / Net I/σ(I): 15.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
1.94-2.046.60.5011.60.5011100
2.04-2.1670.3352.30.3351100
2.16-2.317.20.2343.30.2341100
2.31-2.57.40.1764.50.1761100
2.5-2.747.40.1296.10.1291100
2.74-3.067.40.08690.0861100
3.06-3.537.30.05713.10.0571100
3.53-4.337.20.041170.041199.9
4.33-6.1270.03816.30.038199.7
6.12-115.7426.40.03316.20.033199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASERphasing
PHENIX1.8.4_1492refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.936→65.63 Å / Occupancy max: 1 / Occupancy min: 0.39 / SU ML: 0.18 / σ(F): 1.35 / Phase error: 16.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1884 2089 5.13 %
Rwork0.1604 --
obs0.1618 40682 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.9136 Å2
Refinement stepCycle: LAST / Resolution: 1.936→65.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3988 0 46 320 4354
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064154
X-RAY DIFFRACTIONf_angle_d0.9925606
X-RAY DIFFRACTIONf_dihedral_angle_d13.2511522
X-RAY DIFFRACTIONf_chiral_restr0.045597
X-RAY DIFFRACTIONf_plane_restr0.005739
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9356-1.98060.29651290.22352423X-RAY DIFFRACTION96
1.9806-2.03020.20951440.19092525X-RAY DIFFRACTION100
2.0302-2.08510.21541330.17812537X-RAY DIFFRACTION100
2.0851-2.14640.18771270.1692561X-RAY DIFFRACTION100
2.1464-2.21570.20021470.15912553X-RAY DIFFRACTION100
2.2157-2.29490.21121440.1622522X-RAY DIFFRACTION100
2.2949-2.38680.22621360.16052551X-RAY DIFFRACTION100
2.3868-2.49540.19751560.15812561X-RAY DIFFRACTION100
2.4954-2.6270.19181280.1632572X-RAY DIFFRACTION100
2.627-2.79160.19361380.17122564X-RAY DIFFRACTION100
2.7916-3.00710.18391560.15992566X-RAY DIFFRACTION100
3.0071-3.30970.1871460.15782597X-RAY DIFFRACTION100
3.3097-3.78860.17511420.14382619X-RAY DIFFRACTION100
3.7886-4.7730.15541320.13252638X-RAY DIFFRACTION100
4.773-65.66740.17581310.17792804X-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)
11.7048-0.2555-0.27261.37040.25721.2703-0.0282-0.0684-0.14410.0365-0.0163-0.00650.11320.02460.03490.13490.01160.01110.13770.03580.136123.320217.41619.3049
21.7366-0.04260.01911.6835-0.12531.56330.0634-0.06920.23610.0699-0.0691-0.0184-0.19610.03870.02840.1794-0.00550.00210.0919-0.01570.164426.351844.251214.6143
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A
2X-RAY DIFFRACTION2chain B

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