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Basic information

Entry
Database: PDB / ID: 6anl
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-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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / MAP kinase kinase activity / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN 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 / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / intracellular signal transduction / nuclear speck / 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
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
TAK-715 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 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
DepositionAug 14, 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)42,1142
Polymers41,7151
Non-polymers4001
Water4,143230
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.954, 69.703, 74.294
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / Mutation: C119S, C162S
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-T75 / TAK-715 / N-{4-[2-ETHYL-4-(3-METHYLPHENYL)-1,3-THIAZOL-5-YL]PYRIDIN-2-YL}BENZAMIDE


Mass: 399.508 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21N3OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.17 Å3/Da / Density % sol: 43.35 % / Mosaicity: 0.624 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 15.% PEG 8000, 0.08M NP_HEPES, 0.02M NP_HEPES_Na

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 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: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 25087 / % possible obs: 99.8 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.064 / Χ2: 1.024 / Net I/σ(I): 14
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2-2.0540.25716241.033198.5
2.05-2.14.30.21416271.021199.8
2.1-2.154.40.18916311.0461100
2.15-2.224.40.15716591.0311100
2.22-2.294.40.13816521.0261100
2.29-2.374.40.12116581.0331100
2.37-2.474.40.10716531.031100
2.47-2.584.40.08916501.0131100
2.58-2.714.40.07916521.0351100
2.71-2.884.40.07116901.021100
2.88-3.114.40.06916711.021100
3.11-3.424.30.06516861.012199.9
3.42-3.914.20.05817101.0351100
3.91-4.934.10.04717140.988199.9
4.93-504.10.04518101.011199.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
MOLREPphasing
RefinementResolution: 2→50 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.92 / SU B: 9.014 / SU ML: 0.134 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.211 / ESU R Free: 0.191 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2634 1278 5.1 %RANDOM
Rwork0.2058 ---
obs0.2087 23762 99.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 124.05 Å2 / Biso mean: 37.713 Å2 / Biso min: 16.06 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å20 Å20 Å2
2--0.77 Å2-0 Å2
3----1.42 Å2
Refinement stepCycle: final / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2722 0 29 230 2981
Biso mean--32.72 39.77 -
Num. residues----338
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192832
X-RAY DIFFRACTIONr_angle_refined_deg1.3561.9753848
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7065338
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.93623.985133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.70815486
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7911518
X-RAY DIFFRACTIONr_chiral_restr0.0910.2428
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212152
LS refinement shellResolution: 2.001→2.053 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 99 -
Rwork0.228 1655 -
all-1754 -
obs--96.69 %
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)
16.82453.5697-0.42127.3291-1.720810.1343-0.1554-0.15240.76410.13020.12920.383-1.557-0.40860.02620.38230.1266-0.09560.18720.04560.196318.01918.056-5.656
21.419-0.18251.10862.55072.2224.1834-0.0619-0.14250.2213-0.26530.00880.0525-0.4584-0.11230.05310.07340.00060.01880.11950.00990.089625.3659.382.017
32.55550.97830.71063.3031.08263.2034-0.0244-0.08680.1933-0.1569-0.07080.2534-0.2272-0.29240.09520.02220.018-0.00720.07980.00340.032120.493-9.357-6.541
418.04464.94942.68781.655-0.891310.07090.3397-2.65870.70390.2822-0.66820.1249-0.768-0.32460.32840.24530.1215-0.03110.6057-0.16380.147819.954-16.28910.241
51.6025-0.1560.39711.56230.40863.19430.0622-0.4312-0.23480.14510.0661-0.00150.2564-0.3548-0.12820.0408-0.0441-0.01690.17940.04160.069416.105-23.1657.354
62.63240.46514.01491.40061.888.59230.3295-0.8778-0.37010.4537-0.07040.03471.7677-1.4823-0.25920.742-0.21180.09370.3660.03110.225815.686-30.7615.876
70.89220.10910.2032.25441.16340.9304-0.0115-0.01660.0140.00470.1314-0.2508-0.04880.1169-0.11990.02910.004-0.00370.13390.0040.066430.963-7.141-0.411
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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