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- PDB-8txy: X-ray crystal structure of JRD-SIK1/2i-3 bound to a MARK2-SIK2 chimera -

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Basic information

Entry
Database: PDB / ID: 8txy
TitleX-ray crystal structure of JRD-SIK1/2i-3 bound to a MARK2-SIK2 chimera
ComponentsSerine/threonine-protein kinase MARK2
KeywordsBIOSYNTHETIC PROTEIN / Kinase / enzyme / chimera / inhibitor
Function / homology
Function and homology information


establishment or maintenance of cell polarity regulating cell shape / microtubule bundle / regulation of microtubule binding / mitochondrion localization / autophagy of mitochondrion / tau-protein kinase / establishment or maintenance of epithelial cell apical/basal polarity / regulation of cytoskeleton organization / regulation of axonogenesis / establishment of cell polarity ...establishment or maintenance of cell polarity regulating cell shape / microtubule bundle / regulation of microtubule binding / mitochondrion localization / autophagy of mitochondrion / tau-protein kinase / establishment or maintenance of epithelial cell apical/basal polarity / regulation of cytoskeleton organization / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / axon development / protein kinase activator activity / activation of protein kinase activity / lateral plasma membrane / regulation of microtubule cytoskeleton organization / actin filament / peptidyl-threonine phosphorylation / neuron migration / tau protein binding / microtubule cytoskeleton organization / Wnt signaling pathway / positive regulation of neuron projection development / peptidyl-serine phosphorylation / protein autophosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / cadherin binding / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / lipid binding / magnesium ion binding / mitochondrion / RNA binding / nucleoplasm / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Serine/threonine-protein kinase, active site ...: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated 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
DI(HYDROXYETHYL)ETHER / Chem-SJ0 / Serine/threonine-protein kinase MARK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsRaymond, D.D. / Lemke, C.T. / Shaffer, P.L. / Collins, B. / Steele, R. / Seierstad, M.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.
Authors: Babbe, H. / Sundberg, T.B. / Tichenor, M. / Seierstad, M. / Bacani, G. / Berstler, J. / Chai, W. / Chang, L. / Chung, M. / Coe, K. / Collins, B. / Finley, M. / Guletsky, A. / Lemke, C.T. / ...Authors: Babbe, H. / Sundberg, T.B. / Tichenor, M. / Seierstad, M. / Bacani, G. / Berstler, J. / Chai, W. / Chang, L. / Chung, M. / Coe, K. / Collins, B. / Finley, M. / Guletsky, A. / Lemke, C.T. / Mak, P.A. / Mathur, A. / Mercado-Marin, E.V. / Metkar, S. / Raymond, D.D. / Rives, M.L. / Rizzolio, M. / Shaffer, P.L. / Smith, R. / Smith, J. / Steele, R. / Steffens, H. / Suarez, J. / Tian, G. / Majewski, N. / Volak, L.P. / Wei, J. / Desai, P.T. / Ong, L.L. / Koudriakova, T. / Goldberg, S.D. / Hirst, G. / Kaushik, V.K. / Ort, T. / Seth, N. / Graham, D.B. / Plevy, S. / Venable, J.D. / Xavier, R.J. / Towne, J.E.
History
DepositionAug 24, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase MARK2
B: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,6928
Polymers73,4452
Non-polymers1,2476
Water1,802100
1
A: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4475
Polymers36,7231
Non-polymers7254
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2453
Polymers36,7231
Non-polymers5232
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)121.43, 121.43, 99.64
Angle α, β, γ (deg.)90, 90, 120
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Serine/threonine-protein kinase MARK2 / ELKL motif kinase 1 / EMK-1 / MAP/microtubule affinity-regulating kinase 2 / PAR1 homolog / PAR1 ...ELKL motif kinase 1 / EMK-1 / MAP/microtubule affinity-regulating kinase 2 / PAR1 homolog / PAR1 homolog b / Par-1b / Par1b


Mass: 36722.520 Da / Num. of mol.: 2
Mutation: I59L, K66V V81I, L97I, V113I, M129T, S133K, G134N , S197G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MARK2, EMK1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q7KZI7, non-specific serine/threonine protein kinase, tau-protein kinase
#2: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-SJ0 / N-[(5P,8R)-5-(2-cyano-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}pyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide


Mass: 416.476 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 3 Å3/Da / Density % sol: 58.98 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.8 / Details: 24% PEG 400, 150 mM LiSO4, 100 mM MES ph 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 48682 / % possible obs: 100 % / Redundancy: 10.2 % / CC1/2: 1 / Rmerge(I) obs: 0.05 / Net I/σ(I): 23.6
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 10.2 % / Rmerge(I) obs: 2 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 7948 / CC1/2: 0.657 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (8-JUN-2022)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→46.5 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.91 / SU R Cruickshank DPI: 0.216 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.205 / SU Rfree Blow DPI: 0.176 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.2665 2435 -RANDOM
Rwork0.2392 ---
obs0.2406 48682 100 %-
Displacement parametersBiso mean: 61.63 Å2
Baniso -1Baniso -2Baniso -3
1-2.0396 Å20 Å20 Å2
2--2.0396 Å20 Å2
3----4.0792 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.1→46.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5034 0 26 100 5160
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085244HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.917134HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1895SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes912HARMONIC5
X-RAY DIFFRACTIONt_it5166HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion638SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4008SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion17.56
LS refinement shellResolution: 2.1→2.12 Å
RfactorNum. reflection% reflection
Rfree0.4354 49 -
Rwork0.3676 --
obs0.3713 974 99.8 %

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