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- PDB-4tw9: Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of... -

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Basic information

Entry
Database: PDB / ID: 4tw9
TitleDifluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1delta and epsilon with nanomolar inhibitory activity on cancer cell proliferation
ComponentsCasein kinase I isoform delta
KeywordsTRANSFERASE / CK1delta / CK1epsilon / phosphorylation / small molecule inhibitor
Function / homology
Function and homology information


positive regulation of non-canonical Wnt signaling pathway / protein localization to Golgi apparatus / midbrain dopaminergic neuron differentiation / COPII vesicle coating / microtubule nucleation / tau-protein kinase / non-motile cilium assembly / protein localization to cilium / protein localization to centrosome / COPII-mediated vesicle transport ...positive regulation of non-canonical Wnt signaling pathway / protein localization to Golgi apparatus / midbrain dopaminergic neuron differentiation / COPII vesicle coating / microtubule nucleation / tau-protein kinase / non-motile cilium assembly / protein localization to cilium / protein localization to centrosome / COPII-mediated vesicle transport / tau-protein kinase activity / Golgi organization / Major pathway of rRNA processing in the nucleolus and cytosol / spindle assembly / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / endoplasmic reticulum-Golgi intermediate compartment membrane / AURKA Activation by TPX2 / cellular response to nerve growth factor stimulus / ciliary basal body / circadian regulation of gene expression / spindle microtubule / regulation of circadian rhythm / Wnt signaling pathway / spindle / endocytosis / Regulation of PLK1 Activity at G2/M Transition / Circadian Clock / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / protein kinase activity / cadherin binding / positive regulation of protein phosphorylation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / perinuclear region of cytoplasm / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. ...Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-386 / octyl beta-L-talopyranoside / Casein kinase I isoform delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsRichter, J. / Bischof, J. / Zaja, M. / Kohlhof, H. / Othersen, O. / Vitt, D. / Alscher, V. / Pospiech, I. / Garcia-Reyes, B. / Berg, S. ...Richter, J. / Bischof, J. / Zaja, M. / Kohlhof, H. / Othersen, O. / Vitt, D. / Alscher, V. / Pospiech, I. / Garcia-Reyes, B. / Berg, S. / Leban, J. / Knippschild, U.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1 delta and epsilon with Nanomolar Inhibitory Activity on Cancer Cell Proliferation.
Authors: Richter, J. / Bischof, J. / Zaja, M. / Kohlhof, H. / Othersen, O. / Vitt, D. / Alscher, V. / Pospiech, I. / Garcia-Reyes, B. / Berg, S. / Leban, J. / Knippschild, U.
History
DepositionJun 30, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 30, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Oct 22, 2014Group: Database references
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / database_PDB_caveat / pdbx_validate_chiral / struct_site / struct_site_gen
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id / _chem_comp.mon_nstd_flag / _chem_comp.type / _database_PDB_caveat.text / _pdbx_validate_chiral.auth_atom_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1May 8, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Casein kinase I isoform delta
B: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,19220
Polymers68,6212
Non-polymers2,57118
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3980 Å2
ΔGint-167 kcal/mol
Surface area26920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.049, 135.707, 57.183
Angle α, β, γ (deg.)90.000, 99.420, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B
13A
23B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1116A5 - 85
2116B5 - 85
1126A86 - 300
2126B86 - 300
1134A1006
2134B1006

NCS ensembles :
ID
1
2
3

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Components

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Protein / Sugars , 2 types, 4 molecules AB

#1: Protein Casein kinase I isoform delta / CKId / Tau-protein kinase CSNK1D / Casein Kinase 1 delta


Mass: 34310.613 Da / Num. of mol.: 2 / Fragment: Residues 1-295 / Mutation: yes
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSNK1D, HCKID / Production host: Escherichia coli (E. coli)
References: UniProt: P48730, non-specific serine/threonine protein kinase, tau-protein kinase
#3: Sugar ChemComp-HSJ / octyl beta-L-talopyranoside / octyl beta-L-taloside / octyl L-taloside / octyl taloside


Type: L-saccharide / Mass: 292.369 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H28O6

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Non-polymers , 5 types, 251 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-386 / N-(2,2-difluoro-5H-[1,3]dioxolo[4,5-f]benzimidazol-6-yl)-2-{[2-(trifluoromethoxy)benzoyl]amino}-1,3-thiazole-4-carboxamide


Mass: 527.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H10F5N5O5S
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.92 Å3/Da / Density % sol: 57.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1 M sodium chloride, 1.4 M ammonium sulfate, 0.1 M Bis-Tris

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.541 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jul 5, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.541 Å / Relative weight: 1
ReflectionResolution: 2.4→19.86 Å / Num. obs: 26368 / % possible obs: 86.7 % / Redundancy: 1.7 % / Net I/σ(I): 3.8
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 1.6 % / Mean I/σ(I) obs: 1.2 / % possible all: 92.6

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Processing

Software
NameVersionClassificationNB
REFMAC5.5.0102refinement
SCALAdata scaling
PDB_EXTRACT3.14data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→19.86 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.835 / SU B: 24.642 / SU ML: 0.272 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.568 / ESU R Free: 0.346 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2979 1282 4.9 %RANDOM
Rwork0.2055 25036 --
obs0.2099 26318 86.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 124.79 Å2 / Biso mean: 42.796 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.93 Å20 Å20.32 Å2
2---0.62 Å20 Å2
3---1.66 Å2
Refinement stepCycle: final / Resolution: 2.4→19.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4734 0 158 235 5127
Biso mean--74.1 21.66 -
Num. residues----579
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0225022
X-RAY DIFFRACTIONr_bond_other_d0.0010.023529
X-RAY DIFFRACTIONr_angle_refined_deg1.5191.9956767
X-RAY DIFFRACTIONr_angle_other_deg0.88838519
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7385581
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.71922.983238
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.91915893
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1891538
X-RAY DIFFRACTIONr_chiral_restr0.0820.2694
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025454
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021112
X-RAY DIFFRACTIONr_mcbond_it0.9841.52873
X-RAY DIFFRACTIONr_mcbond_other0.2451.51190
X-RAY DIFFRACTIONr_mcangle_it1.68124613
X-RAY DIFFRACTIONr_scbond_it2.92232149
X-RAY DIFFRACTIONr_scangle_it4.34.52152
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
11032LOOSE POSITIONAL0.615
11032LOOSE THERMAL1.8110
22950LOOSE POSITIONAL0.485
22950LOOSE THERMAL1.9810
341MEDIUM POSITIONAL0.350.5
341MEDIUM THERMAL0.432
LS refinement shellResolution: 2.4→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 111 -
Rwork0.264 1942 -
all-2053 -
obs--91.57 %
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)
16.11452.3016-0.39833.5353-0.5290.5198-0.03590.29810.0827-0.10020.09410.2726-0.076-0.2876-0.05820.09480.0231-0.0120.17450.00210.2332-3.5574-6.81764.5122
24.68211.03511.13054.3955-0.33371.9788-0.10060.19540.2156-0.1701-0.0061-0.4083-0.05840.41490.10670.0189-0.02450.04420.1085-0.05960.24929.7756-32.15314.6937
32.7031-1.1767-0.16363.24890.59891.7461-0.0154-0.1536-0.07130.14390.0183-0.04890.0215-0.0955-0.00290.0343-0.0008-0.00270.00240.00610.125317.65052.932414.7098
43.0816-0.40450.75092.4682-0.84851.83810.0683-0.27340.1250.0868-0.0296-0.06810.0762-0.0758-0.03870.0147-0.0280.01210.0356-0.04450.11377.1968-43.328310.813
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 85
2X-RAY DIFFRACTION2B1 - 85
3X-RAY DIFFRACTION3A86 - 295
4X-RAY DIFFRACTION4B86 - 295

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