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- PDB-6hwv: Crystal structure of p38alpha in complex with a photoswitchable 2... -

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Basic information

Entry
Database: PDB / ID: 6hwv
TitleCrystal structure of p38alpha in complex with a photoswitchable 2-Azoimidazol-based Inhibitor (compound 3)
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / p38alpha / MAPK14 / photoswitchable / Azothiazol
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 / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 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 / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / 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 / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / signal transduction in response to DNA damage / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / negative regulation of hippo signaling / positive regulation of myoblast differentiation / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / p38MAPK events / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / positive regulation of interleukin-12 production / positive regulation of erythrocyte differentiation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import across plasma membrane / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 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 / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / chemotaxis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / 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 / 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 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-GEW / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMueller, M.P. / Rauh, D.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
CitationJournal: Photochem. Photobiol. Sci. / Year: 2019
Title: 2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach.
Authors: Schehr, M. / Ianes, C. / Weisner, J. / Heintze, L. / Muller, M.P. / Pichlo, C. / Charl, J. / Brunstein, E. / Ewert, J. / Lehr, M. / Baumann, U. / Rauh, D. / Knippschild, U. / Peifer, C. / Herges, R.
History
DepositionOct 15, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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)42,9545
Polymers41,4941
Non-polymers1,4604
Water4,864270
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1580 Å2
ΔGint16 kcal/mol
Surface area17150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.010, 69.980, 74.710
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: 41494.277 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 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical ChemComp-GEW / 3-(2,5-dimethoxyphenyl)-~{N}-[4-[5-(4-fluorophenyl)-2-[(~{E})-(4-fluorophenyl)diazenyl]-3-methyl-imidazol-4-yl]pyridin-2-yl]propanamide


Mass: 582.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H28F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 270 / 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: 43.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES pH 5.6-6.2, 20-30 % PEG4000, 40mM BOG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→49.1 Å / Num. obs: 40470 / % possible obs: 100 % / Redundancy: 13.1 % / Rmerge(I) obs: 0.078 / Rrim(I) all: 0.081 / Net I/σ(I): 20.6
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 13.3 % / Rmerge(I) obs: 0.808 / Mean I/σ(I) obs: 3 / Num. unique obs: 6261 / Rrim(I) all: 0.84 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5n63

5n63


Resolution: 1.7→37.355 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.88
RfactorNum. reflection% reflection
Rfree0.1969 2023 5 %
Rwork0.1796 --
obs0.1805 40463 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→37.355 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2712 0 103 270 3085
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062932
X-RAY DIFFRACTIONf_angle_d0.9563984
X-RAY DIFFRACTIONf_dihedral_angle_d13.961796
X-RAY DIFFRACTIONf_chiral_restr0.054447
X-RAY DIFFRACTIONf_plane_restr0.006499
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.74250.30961410.28092686X-RAY DIFFRACTION100
1.7425-1.78960.25961440.23162730X-RAY DIFFRACTION100
1.7896-1.84230.23461420.21062688X-RAY DIFFRACTION100
1.8423-1.90180.21091420.20062702X-RAY DIFFRACTION100
1.9018-1.96970.26181420.21452723X-RAY DIFFRACTION100
1.9697-2.04860.20841430.19572704X-RAY DIFFRACTION100
2.0486-2.14180.21321430.18172731X-RAY DIFFRACTION100
2.1418-2.25470.21171440.17892728X-RAY DIFFRACTION100
2.2547-2.3960.22021440.18192743X-RAY DIFFRACTION100
2.396-2.58090.18941450.18672741X-RAY DIFFRACTION100
2.5809-2.84060.21131450.18242757X-RAY DIFFRACTION100
2.8406-3.25140.20681460.18462773X-RAY DIFFRACTION100
3.2514-4.09560.18631480.15722809X-RAY DIFFRACTION100
4.0956-37.3640.14961540.16232925X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -11.7282 Å / Origin y: -4.5177 Å / Origin z: 18.1505 Å
111213212223313233
T0.1153 Å20.0171 Å2-0.008 Å2-0.0626 Å2-0.0088 Å2--0.0678 Å2
L0.8642 °20.1219 °20.0225 °2-0.5865 °20.024 °2--0.5389 °2
S0.0093 Å °0.0143 Å °0.0247 Å °0.0155 Å °-0.0067 Å °0.0009 Å °-0.073 Å °-0.0239 Å °-0.0004 Å °
Refinement TLS groupSelection details: (chain A and resseq 5:352)

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