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Entry
Database: PDB / ID: 5wjj
TitleStructure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors
ComponentsMitogen-activated protein kinase 14
KeywordsTransferase/Transferase Inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / D-glucose import / p38MAPK cascade / ERK/MAPK targets / Regulation of MITF-M-dependent genes involved in pigmentation / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / signal transduction in response to DNA damage / cellular response to vascular endothelial growth factor stimulus / MAP kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / positive regulation of brown fat cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import / NOD1/2 Signaling Pathway / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / chemotaxis / spindle pole / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / MAPK cascade / cellular response to lipopolysaccharide / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / angiogenesis / protein phosphatase binding / secretory granule lumen / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / nuclear speck / intracellular signal transduction / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / glutamatergic synapse / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / ATP binding
Similarity search - Function
Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-AQY / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsSnell, G.P. / Okada, K. / Bragstad, K. / Sang, B.-C.
CitationJournal: Bioorg. Med. Chem. / Year: 2018
Title: Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.
Authors: Kaieda, A. / Takahashi, M. / Takai, T. / Goto, M. / Miyazaki, T. / Hori, Y. / Unno, S. / Kawamoto, T. / Tanaka, T. / Itono, S. / Takagi, T. / Hamada, T. / Shirasaki, M. / Okada, K. / Snell, ...Authors: Kaieda, A. / Takahashi, M. / Takai, T. / Goto, M. / Miyazaki, T. / Hori, Y. / Unno, S. / Kawamoto, T. / Tanaka, T. / Itono, S. / Takagi, T. / Hamada, T. / Shirasaki, M. / Okada, K. / Snell, G. / Bragstad, K. / Sang, B.C. / Uchikawa, O. / Miwatashi, S.
History
DepositionJul 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
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: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1692
Polymers41,7151
Non-polymers4541
Water6,846380
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.813, 69.974, 73.878
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / ...MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / MAX-interacting protein 2 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Stress-activated protein kinase 2a / SAPK2a


Mass: 41714.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A / Plasmid: pFastBacHT / Production host: Baculovirus expression vector pFastBac1-HM / Strain (production host): Sf9
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-AQY / N-{4-[2-(4-fluoro-3-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]pyridin-2-yl}-2-methyl-1-oxo-1lambda~5~-pyridine-4-carboxamide


Mass: 454.456 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / 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: 43.13 % / Mosaicity: 0.291 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 18.% PEG 3350, 0.06M MES, 0.04M MES_Na

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 11, 2007
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.6→50.7 Å / Num. obs: 46461 / % possible obs: 95.5 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.068 / Χ2: 1.014 / Net I/σ(I): 11.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsΧ2Diffraction-ID% possible all
1.6-1.642.60.4280.979160
1.64-1.683.20.4411.01180.2
1.68-1.723.70.3941.042193.3
1.72-1.774.20.3290.985199.2
1.77-1.834.50.2781.025199.9
1.83-1.94.60.2141.016199.9
1.9-1.974.60.1631.0461100
1.97-2.064.60.1221.0151100
2.06-2.174.60.0921.0181100
2.17-2.314.60.0791.0021100
2.31-2.494.60.071.0081100
2.49-2.744.60.0671.002199.9
2.74-3.134.40.0681.016199.9
3.13-3.954.30.0551.055199.9
3.95-504.30.0340.971199.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data collection
HKL-2000data scaling
MOLREPphasing
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→50 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.932 / SU B: 4.27 / SU ML: 0.076 / Cross valid method: THROUGHOUT / ESU R: 0.105 / ESU R Free: 0.105 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23712 2346 5.1 %RANDOM
Rwork0.20033 ---
obs0.20221 44054 95.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.054 Å2
Baniso -1Baniso -2Baniso -3
1--0.62 Å20 Å20 Å2
2--1.46 Å2-0 Å2
3----0.84 Å2
Refinement stepCycle: 1 / Resolution: 1.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2712 0 34 380 3126
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192853
X-RAY DIFFRACTIONr_bond_other_d0.0020.022689
X-RAY DIFFRACTIONr_angle_refined_deg1.3221.9743887
X-RAY DIFFRACTIONr_angle_other_deg0.88536182
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0735346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.35723.897136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.53315481
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9711519
X-RAY DIFFRACTIONr_chiral_restr0.0740.2431
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213211
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02654
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5421.1831360
X-RAY DIFFRACTIONr_mcbond_other0.5421.1821359
X-RAY DIFFRACTIONr_mcangle_it0.9751.7681696
X-RAY DIFFRACTIONr_mcangle_other0.9751.7691697
X-RAY DIFFRACTIONr_scbond_it0.5671.2641493
X-RAY DIFFRACTIONr_scbond_other0.5341.2571456
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.9241.8572131
X-RAY DIFFRACTIONr_long_range_B_refined5.65611.3513694
X-RAY DIFFRACTIONr_long_range_B_other5.36910.0693416
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.598→1.639 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 100 -
Rwork0.284 2013 -
obs--59.72 %
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)
13.8794-0.74831.47284.5449-1.50676.30730.06240.0003-0.3235-0.18990.05690.1040.5446-0.2762-0.11930.1037-0.0445-0.00040.06370.03060.052517.085-17.5895.58
21.72460.3594-0.92950.9630.35922.5779-0.02630.1367-0.0430.00620.01750.01080.1482-0.04250.00870.04220.0087-0.00740.02770.0050.011725.068-9.176-1.944
32.5967-0.5209-0.4992.84150.491.8916-0.01260.0594-0.1729-0.0047-0.02040.20060.1248-0.18310.0330.0272-0.00550.00210.0206-0.00080.022519.7559.2636.367
410.1591-2.6594-0.66661.0583-1.36256.82980.06461.4476-0.5894-0.1796-0.320.08180.5521-0.22540.25540.1557-0.07660.07130.2599-0.12960.089419.50416.438-9.856
51.4566-0.19050.45651.2160.13552.4313-0.01850.12550.1356-0.13470.0630.0024-0.1479-0.1455-0.04450.0446-0.00130.00760.03350.02060.018716.00423.31-7.424
61.3932-0.2584-1.9590.53271.45796.50370.08240.36890.1828-0.2348-0.01340.084-0.9966-0.5094-0.0690.2370.0281-0.02120.14060.01840.156815.89130.825-4.673
70.471-0.2976-0.12061.78370.9180.64-0.0223-0.00390.0054-0.00960.0827-0.11290.03180.081-0.06050.0498-0.00310.01720.05140.00290.019830.7947.2940.484
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 49
2X-RAY DIFFRACTION2A50 - 115
3X-RAY DIFFRACTION3A119 - 173
4X-RAY DIFFRACTION4A184 - 203
5X-RAY DIFFRACTION5A204 - 254
6X-RAY DIFFRACTION6A255 - 280
7X-RAY DIFFRACTION7A281 - 352

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