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- PDB-8r4u: Structure of salt-inducible kinase 3 with inhibitors -

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Basic information

Entry
Database: PDB / ID: 8r4u
TitleStructure of salt-inducible kinase 3 with inhibitors
Components
  • Serine/threonine-protein kinase SIK3
  • scFvH1
KeywordsLIGASE / kinase / inhibitor complex / drug design / ampk-like kinase / UBA
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
: / Serine/threonine-protein kinase SIK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.416 Å
AuthorsKack, H. / Oster, L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Biol.Chem. / Year: 2024
Title: The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity.
Authors: Oster, L. / Castaldo, M. / de Vries, E. / Edfeldt, F. / Pemberton, N. / Gordon, E. / Cederblad, L. / Kack, H.
History
DepositionNov 14, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 8, 2024Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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: scFvH1
C: Serine/threonine-protein kinase SIK3
D: scFvH1
E: Serine/threonine-protein kinase SIK3
F: scFvH1
G: Serine/threonine-protein kinase SIK3
H: scFvH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,57116
Polymers261,2008
Non-polymers2,3728
Water6,233346
1
A: Serine/threonine-protein kinase SIK3
B: scFvH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9895
Polymers65,3002
Non-polymers6893
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Serine/threonine-protein kinase SIK3
D: scFvH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7973
Polymers65,3002
Non-polymers4971
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Serine/threonine-protein kinase SIK3
F: scFvH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8934
Polymers65,3002
Non-polymers5932
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: Serine/threonine-protein kinase SIK3
H: scFvH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8934
Polymers65,3002
Non-polymers5932
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.074, 112.841, 127.118
Angle α, β, γ (deg.)66.32, 81.42, 90.1
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Serine/threonine-protein kinase SIK3


Mass: 37888.852 Da / Num. of mol.: 4 / Mutation: C121S, C181S, C333S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIK3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y2K2
#2: Protein
scFvH1


Mass: 27411.029 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Chemical
ChemComp-XW3 / 8-[(5-azanyl-1,3-dioxan-2-yl)methyl]-6-[2-chloranyl-4-(3-fluoranylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one


Mass: 496.921 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H22ClFN6O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 346 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.13 Å3/Da / Density % sol: 60.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5 / Details: 1.3 M LiSO4 and 0.1 M Hepes pH 7.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.416→114.84 Å / Num. obs: 67135 / % possible obs: 57.7 % / Redundancy: 1.9 % / CC1/2: 0.985 / Net I/σ(I): 3.8
Reflection shellResolution: 2.45→2.76 Å / Redundancy: 1.9 % / Num. unique obs: 3359 / CC1/2: 0.725 / % possible all: 9.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.416→114.84 Å / Cor.coef. Fo:Fc: 0.857 / Cor.coef. Fo:Fc free: 0.809 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.407
RfactorNum. reflection% reflectionSelection details
Rfree0.2653 3056 -RANDOM
Rwork0.2278 ---
obs0.2296 62579 51.5 %-
Displacement parametersBiso mean: 35.42 Å2
Baniso -1Baniso -2Baniso -3
1--7.9395 Å20.07 Å20.3297 Å2
2---3.221 Å20.3743 Å2
3---11.1604 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: LAST / Resolution: 2.416→114.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17119 0 160 346 17625
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00717667HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9523936HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5995SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2998HARMONIC5
X-RAY DIFFRACTIONt_it17667HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion2258SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact13180SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion20.14
LS refinement shellResolution: 2.42→2.62 Å
RfactorNum. reflection% reflection
Rfree0.3466 76 -
Rwork0.2845 --
obs0.2882 1252 4.74 %
Refinement TLS params.

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)
12.31440.143-0.53580.77970.22891.1434-0.05320.15580.04890.1558-0.0744-0.10130.0489-0.10130.1276-0.19340.004-0.0509-0.09020.07170.143-28.2277-31.325-34.4557
23.0975-0.00930.44662.4927-0.95191.5480.0640.1021-0.1430.1021-0.11090.0918-0.1430.09180.047-0.3504-0.01220.0117-0.2696-00.07517.476-17.0302-45.1763
33.81470.14910.87710.6048-0.75152.2545-0.09650.15060.04970.1506-0.13390.13120.04970.13120.2304-0.2285-0.01650.0314-0.2332-0.07440.1111-28.684233.3136-32.1107
42.9467-0.27330.52923.03550.8711.80130.0150.02350.10270.0235-0.0669-0.10060.1027-0.10060.0519-0.3607-0.04880.0527-0.27120.03870.0474-63.603520.5419-43.4449
52.6022-0.2262-0.60060.8815-0.31591.5789-0.0839-0.17630.0506-0.1763-0.06480.17640.05060.17640.1488-0.2590.0126-0.0122-0.1255-0.07630.100815.6111-25.7736-89.2526
63.2918-0.8957-0.01523.09810.60791.45040.0062-0.0807-0.1546-0.0807-0.1982-0.1048-0.1546-0.10480.192-0.38430.00810.0007-0.2780.02940.1094-20.1336-11.3464-78.6888
73.6834-0.18990.86520.58710.28141.9824-0.0018-0.14460.1078-0.1446-0.0729-0.08510.1078-0.08510.0747-0.2590.01930.0403-0.22680.07710.1301-45.099538.9389-88.4234
84.0655-0.74021.0362.7215-1.03382.01050.1582-0.07610.178-0.0761-0.15940.0720.1780.0720.0012-0.38090.01640.0315-0.2655-0.01260.025-11.500325.6788-79.9227
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A61 - 384
2X-RAY DIFFRACTION1{ A|* }A459
3X-RAY DIFFRACTION2{ B|* }B1 - 250
4X-RAY DIFFRACTION3{ C|* }C62 - 384
5X-RAY DIFFRACTION3{ C|* }C459
6X-RAY DIFFRACTION4{ D|* }D1 - 250
7X-RAY DIFFRACTION5{ E|* }E61 - 384
8X-RAY DIFFRACTION5{ E|* }E459
9X-RAY DIFFRACTION6{ F|* }F1 - 250
10X-RAY DIFFRACTION7{ G|* }G62 - 384
11X-RAY DIFFRACTION7{ G|* }G459
12X-RAY DIFFRACTION8{ H|* }H1 - 250

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