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

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Basic information

Entry
Database: PDB / ID: 4nbn
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 / 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
Chem-2J7 / PHOSPHATE ION / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 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 1.0Dec 18, 2013Provider: 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)65,80512
Polymers64,6282
Non-polymers1,17710
Water5,188288
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5240 Å2
ΔGint-72 kcal/mol
Surface area20690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.807, 115.807, 79.672
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-561-

HOH

21A-607-

HOH

31B-603-

HOH

41B-640-

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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-2J7 / 2,2'-[pyrimidine-4,6-diylbis(iminomethanediyl)]diphenol


Mass: 322.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N4O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 2.07 Å3/Da / Density % sol: 40.48 %
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: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 16, 2010
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 104780 / % possible obs: 98.9 % / Redundancy: 5 % / Biso Wilson estimate: 22.35 Å2 / Rmerge(I) obs: 0.053 / Χ2: 1.034 / Net I/σ(I): 16.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.75-1.814.30.45896901.014191.8
1.81-1.894.90.322104441.07199.5
1.89-1.975.10.204104820.982199.4
1.97-2.075.20.138105081.029199.5
2.07-2.25.20.095105311.025199.7
2.2-2.385.20.074105671.091199.7
2.38-2.615.20.057105361.071199.9
2.61-2.995.20.047105941.026199.9
2.99-3.775.10.054106451.0041100
3.77-5050.033107831.022199.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.5.5phasing
PHENIX1.8.4_1492refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→50 Å / Occupancy max: 1 / Occupancy min: 0.35 / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.89 / Phase error: 17.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1875 2970 5.16 %random
Rwork0.1589 ---
obs0.1604 57611 96.61 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 123.68 Å2 / Biso mean: 28.2358 Å2 / Biso min: 10.87 Å2
Refinement stepCycle: LAST / Resolution: 1.75→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4003 0 69 288 4360
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124192
X-RAY DIFFRACTIONf_angle_d1.2985658
X-RAY DIFFRACTIONf_chiral_restr0.067600
X-RAY DIFFRACTIONf_plane_restr0.008717
X-RAY DIFFRACTIONf_dihedral_angle_d13.5731525
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 21

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7031-1.7310.31081010.25271943204474
1.731-1.76090.28931060.24142139224580
1.7609-1.79290.26621440.21442369251390
1.7929-1.82740.23741530.18832574272798
1.8274-1.86470.19151420.1752603274598
1.8647-1.90520.21161480.15722631277999
1.9052-1.94960.22321340.16322639277399
1.9496-1.99830.21121430.15392617276099
1.9983-2.05240.16841430.15452640278399
2.0524-2.11280.21961410.15882656279799
2.1128-2.1810.16691440.15592635277999
2.181-2.25890.19871490.15612652280199
2.2589-2.34940.21181400.15642663280399
2.3494-2.45630.19471550.154726672822100
2.4563-2.58580.23381430.16322669281299
2.5858-2.74780.17481500.168426912841100
2.7478-2.960.19721510.160426892840100
2.96-3.25790.17841580.15727082866100
3.2579-3.72930.16151450.139927432888100
3.7293-4.69850.14471420.130227852927100
4.6985-81.98270.18461380.18032928306699
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)
11.9545-0.3203-0.31271.73720.33531.6562-0.0415-0.0635-0.1870.0324-0.0025-0.0080.10950.04470.03670.11090.00680.01110.11590.03580.103823.404517.446519.3756
21.9150.1083-0.04571.7926-0.14921.76370.0575-0.08750.26240.0753-0.0599-0.0369-0.20610.05860.02320.1675-0.0028-0.00470.073-0.0080.14126.442944.255414.7859
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain AA25 - 292
2X-RAY DIFFRACTION2chain BB30 - 291

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