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- PDB-4n7m: Tailoring Small Molecules for an Allosteric Site on Procaspase-6 -

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Basic information

Entry
Database: PDB / ID: 4n7m
TitleTailoring Small Molecules for an Allosteric Site on Procaspase-6
ComponentsCaspase-6
KeywordsHYDROLASE / procaspse-6 / caspase-6 zymogen / allosteric / Structure Based Drug Design / cysteine protease
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
3-(pyrrolidin-1-yl)isoquinolin-1(2H)-one / PHOSPHATE ION / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.125 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 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Dec 10, 2014Group: Structure summary
Revision 1.3Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _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)65,3178
Polymers64,6282
Non-polymers6896
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-51 kcal/mol
Surface area20660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.700, 115.700, 79.691
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-612-

HOH

21B-562-

HOH

31B-599-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1

Dom-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1PHEPHESERSERchain AAA25 - 2925 - 272
2METMETLYSLYSchain BBB30 - 29110 - 271

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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 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P55212, caspase-6
#2: Chemical ChemComp-2GQ / 3-(pyrrolidin-1-yl)isoquinolin-1(2H)-one


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.: 5 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / 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: 5.0.1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 16, 2010
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.123→115.593 Å / Num. all: 31101 / Num. obs: 31101 / % possible obs: 100 % / Redundancy: 9.9 % / Rsym value: 0.084 / Net I/σ(I): 22.3
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value
2.12-2.24100.5461.44445244480.546
2.24-2.3710.10.4121.94282742490.412
2.37-2.5410.10.2882.73987839490.288
2.54-2.7410.10.2043.83754137270.204
2.74-3100.12963442934300.129
3-3.36100.07510.33120631330.075
3.36-3.889.80.04516.72724127760.045
3.88-4.759.60.03420.82290623800.034
4.75-6.719.30.03321.41759118830.033
6.71-115.5938.90.02130997211260.021

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASERphasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.125→81.812 Å / Occupancy max: 1 / Occupancy min: 0.39 / FOM work R set: 0.8835 / SU ML: 0.22 / σ(F): 1.62 / Phase error: 18.25 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1987 1598 5.15 %random
Rwork0.1592 ---
obs0.1612 31042 99.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 142.44 Å2 / Biso mean: 32.1219 Å2 / Biso min: 11.49 Å2
Refinement stepCycle: LAST / Resolution: 2.125→81.812 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3980 0 41 269 4290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0134111
X-RAY DIFFRACTIONf_angle_d1.3975546
X-RAY DIFFRACTIONf_chiral_restr0.091597
X-RAY DIFFRACTIONf_plane_restr0.008718
X-RAY DIFFRACTIONf_dihedral_angle_d14.2711509
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2228X-RAY DIFFRACTION6.718TORSIONAL
12B2228X-RAY DIFFRACTION6.718TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1246-2.19310.22831460.18222607275399
2.1931-2.27150.22961480.173626432791100
2.2715-2.36250.23781300.169926212751100
2.3625-2.470.24071600.167726312791100
2.47-2.60020.23621410.172226562797100
2.6002-2.76320.2371480.180426422790100
2.7632-2.97650.21921490.160926602809100
2.9765-3.27610.17521570.151626522809100
3.2761-3.75010.17521430.136227032846100
3.7501-4.72470.15881410.129527272868100
4.7247-81.87290.19841350.185429023037100
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)
12.4872-0.45850.32632.0432-0.62081.8998-0.0452-0.01130.23220.0348-0.01590.0065-0.1596-0.08680.06390.14340.0117-0.0180.1674-0.0470.1508-22.8767-17.391219.3324
22.52830.24030.1242.45690.46052.33250.1027-0.1097-0.2450.0782-0.08940.01160.2468-0.04760.00370.20880.00250.00140.09070.02450.1769-26.3644-44.241114.6162
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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