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- PDB-5w4w: Identification and Profiling of a Selective and Brain Penetrant R... -

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Basic information

Entry
Database: PDB / ID: 5w4w
TitleIdentification and Profiling of a Selective and Brain Penetrant Radioligand for In Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors
ComponentsCasein kinase I isoform delta
KeywordsTRANSFERASE/INHIBITOR / kinase / inhibitor / TRANSFERASE-INHIBITOR complex
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-9WG / Casein kinase I isoform delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.99 Å
AuthorsLiu, S.
CitationJournal: ACS Chem Neurosci / Year: 2017
Title: Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors.
Authors: Wager, T.T. / Galatsis, P. / Chandrasekaran, R.Y. / Butler, T.W. / Li, J. / Zhang, L. / Mente, S. / Subramanyam, C. / Liu, S. / Doran, A.C. / Chang, C. / Fisher, K. / Grimwood, S. / Hedde, J. ...Authors: Wager, T.T. / Galatsis, P. / Chandrasekaran, R.Y. / Butler, T.W. / Li, J. / Zhang, L. / Mente, S. / Subramanyam, C. / Liu, S. / Doran, A.C. / Chang, C. / Fisher, K. / Grimwood, S. / Hedde, J.R. / Marconi, M. / Schildknegt, K.
History
DepositionJun 13, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _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
C: Casein kinase I isoform delta
D: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)156,87923
Polymers154,1494
Non-polymers2,73019
Water9,350519
1
A: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1485
Polymers38,5371
Non-polymers6114
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4368
Polymers38,5371
Non-polymers8997
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2446
Polymers38,5371
Non-polymers7075
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Casein kinase I isoform delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0524
Polymers38,5371
Non-polymers5143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.884, 84.584, 89.042
Angle α, β, γ (deg.)70.37, 74.27, 86.77
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 38537.223 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSNK1D, HCKID
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P48730, non-specific serine/threonine protein kinase, tau-protein kinase
#2: Chemical
ChemComp-9WG / 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one


Mass: 322.336 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H15FN4O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 519 / 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: 2.16 Å3/Da / Density % sol: 43.15 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 17, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.99→80.79 Å / Num. obs: 86009 / % possible obs: 96.4 % / Redundancy: 2 % / Biso Wilson estimate: 33.63 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 7.1
Reflection shellResolution: 1.99→2.09 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.393 / Mean I/σ(I) obs: 2 / Num. unique obs: 12461 / % possible all: 95.5

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.99→20.06 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.914 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.194 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.168 / SU Rfree Blow DPI: 0.146 / SU Rfree Cruickshank DPI: 0.158
RfactorNum. reflection% reflectionSelection details
Rfree0.215 3758 4.94 %RANDOM
Rwork0.18 ---
obs0.181 76032 96.3 %-
Displacement parametersBiso mean: 41.86 Å2
Baniso -1Baniso -2Baniso -3
1-0.9744 Å20.4624 Å20.3561 Å2
2---4.093 Å210.8647 Å2
3---3.1186 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 1.99→20.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9420 0 171 519 10110
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019879HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9813343HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3504SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes210HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1551HARMONIC5
X-RAY DIFFRACTIONt_it9879HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion18.36
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1178SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact11332SEMIHARMONIC4
LS refinement shellResolution: 1.99→2.04 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.214 157 4.81 %
Rwork0.209 3109 -
all0.209 3266 -
obs--95.08 %
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)
10.5803-0.0828-0.81190.45121.0662.72230.12760.14060.0704-0.136-0.08190.0158-0.4018-0.4017-0.0456-0.0390.09440.02090.04550.0272-0.040954.193785.6986107.7914
20.65260.06820.84810.46170.89322.70570.1279-0.1803-0.04280.0869-0.11290.01440.3551-0.4675-0.015-0.0476-0.0694-0.04720.08260.0006-0.063735.113884.1896-7.8229
30.44430.37420.54910.8070.85393.25520.05790.0659-0.12040.02050.1966-0.19790.16480.4033-0.2545-0.12760.0409-0.04310.0598-0.0674-0.0015-0.291616.887230.4071
40.3247-0.331-0.50610.82990.81353.34410.0786-0.00870.1086-0.03990.1787-0.1681-0.17620.4005-0.2572-0.1254-0.0020.01720.0904-0.07290.004847.863939.9248-11.9142
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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