[English] 日本語
Yorodumi
- PDB-6anl: Structure-based Design, Synthesis, and Biological Evaluation of I... -

+
Open data


ID or keywords:

Loading...

-
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 14MAPK14
KeywordsTRANSFERASE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions / cartilage condensation ...positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / stress-activated protein kinase signaling cascade / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / response to dietary excess / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / 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 / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / NOD1/2 Signaling Pathway / bone development / cell morphogenesis / platelet activation / osteoblast differentiation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / Oxidative Stress Induced Senescence / secretory granule lumen / cellular response to lipopolysaccharide / 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 / glutamatergic synapse / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
Components

#1: Protein Mitogen-activated protein kinase 14 / MAPK14 / 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 / Water


Mass: 18.015 Da / Num. of mol.: 230 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more