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- PDB-8oku: Salt-Inducible Kinase 3 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8oku
TitleSalt-Inducible Kinase 3 in complex with an inhibitor
ComponentsSerine/threonine-protein kinase SIK3
KeywordsSIGNALING PROTEIN / Kinase UBA Inhibitor
Function / homology
Function and homology information


positive regulation of TORC2 signaling / tau-protein kinase activity / positive regulation of TORC1 signaling / microtubule cytoskeleton organization / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity ...positive regulation of TORC2 signaling / tau-protein kinase activity / positive regulation of TORC1 signaling / microtubule cytoskeleton organization / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / magnesium ion binding / ATP binding / cytoplasm
Similarity search - Function
Salt-Inducible kinase, catalytic domain / Protein kinase SIK3 UBA domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / 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. ...Salt-Inducible kinase, catalytic domain / Protein kinase SIK3 UBA domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / 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
Similarity search - Domain/homology
Chem-VRU / Serine/threonine-protein kinase SIK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsFlower, T.G. / Leonard, P.M. / Lamers, M.B.A.C. / Mollat, P.
Funding support France, 1items
OrganizationGrant numberCountry
Not funded France
CitationJournal: J.Med.Chem. / Year: 2024
Title: Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.
Authors: Temal-Laib, T. / Peixoto, C. / Desroy, N. / De Lemos, E. / Bonnaterre, F. / Bienvenu, N. / Picolet, O. / Sartori, E. / Bucher, D. / Lopez-Ramos, M. / Roca Magadan, C. / Laenen, W. / Flower, ...Authors: Temal-Laib, T. / Peixoto, C. / Desroy, N. / De Lemos, E. / Bonnaterre, F. / Bienvenu, N. / Picolet, O. / Sartori, E. / Bucher, D. / Lopez-Ramos, M. / Roca Magadan, C. / Laenen, W. / Flower, T. / Mollat, P. / Bugaud, O. / Touitou, R. / Pereira Fernandes, A. / Lavazais, S. / Monjardet, A. / Borgonovi, M. / Gosmini, R. / Brys, R. / Amantini, D. / De Vos, S. / Andrews, M.
History
DepositionMar 29, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase SIK3
B: Serine/threonine-protein kinase SIK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,6714
Polymers80,8002
Non-polymers8712
Water1267
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-14 kcal/mol
Surface area31840 Å2
Unit cell
Length a, b, c (Å)174.553, 174.553, 152.308
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Serine/threonine-protein kinase SIK3 / Salt-inducible kinase 3 / SIK-3 / Serine/threonine-protein kinase QSK


Mass: 40400.027 Da / Num. of mol.: 2 / Mutation: T221D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIK3, KIAA0999, QSK, L19 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y2K2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VRU / ~{N}-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxy-benzamide


Mass: 435.476 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H25N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 4.14 Å3/Da / Density % sol: 70.33 %
Crystal growTemperature: 282.15 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.1 M sodium formate pH 7.0, 12% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3.1→107.29 Å / Num. obs: 25156 / % possible obs: 99.3 % / Redundancy: 9.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.218 / Net I/σ(I): 7.2
Reflection shellResolution: 3.1001→3.2242 Å / Rmerge(I) obs: 2.887 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 2611 / CC1/2: 0.536 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5refinement
Aimlessdata scaling
MOSFLMdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→107.29 Å / SU ML: 0.49 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2589 1248 4.97 %
Rwork0.2141 --
obs0.2164 25096 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.1→107.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5370 0 64 7 5441
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0115557
X-RAY DIFFRACTIONf_angle_d1.3237488
X-RAY DIFFRACTIONf_dihedral_angle_d12.1133346
X-RAY DIFFRACTIONf_chiral_restr0.071809
X-RAY DIFFRACTIONf_plane_restr0.009949

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