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- PDB-6hwt: Crystal structure of p38alpha in complex with a reduced photoswit... -

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Basic information

Entry
Database: PDB / ID: 6hwt
TitleCrystal structure of p38alpha in complex with a reduced photoswitchable 2-Azothiazol-based Inhibitor (compound 31)
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 / 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 / cartilage condensation ...stress-activated protein kinase signaling cascade / 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 / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / positive regulation of erythrocyte differentiation / osteoclast differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / chemotaxis / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / secretory granule lumen / 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 / glutamatergic synapse / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase 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
Chem-GXH / 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)42,9415
Polymers41,4941
Non-polymers1,4474
Water3,693205
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1560 Å2
ΔGint15 kcal/mol
Surface area17110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.510, 69.810, 74.570
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 natural source / Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical ChemComp-GXH / 3-(2,5-dimethoxyphenyl)-~{N}-[4-[4-(4-fluorophenyl)-2-(2-phenylhydrazinyl)-1,3-thiazol-5-yl]pyridin-2-yl]propanamide


Mass: 569.649 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.19 Å3/Da / Density % sol: 43.86 %
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: 0.977928 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977928 Å / Relative weight: 1
ReflectionResolution: 1.7→49.3 Å / Num. obs: 39982 / % possible obs: 98.5 % / Redundancy: 8.4 % / Rmerge(I) obs: 0.065 / Rrim(I) all: 0.069 / Net I/σ(I): 17
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 8.6 % / Rmerge(I) obs: 0.803 / Num. unique obs: 6261 / Rrim(I) all: 0.858 / % 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→49.257 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.93
RfactorNum. reflection% reflection
Rfree0.2345 2000 5.01 %
Rwork0.2021 --
obs0.2037 39952 98.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→49.257 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2706 0 101 205 3012
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052919
X-RAY DIFFRACTIONf_angle_d0.9653965
X-RAY DIFFRACTIONf_dihedral_angle_d12.5251791
X-RAY DIFFRACTIONf_chiral_restr0.048449
X-RAY DIFFRACTIONf_plane_restr0.004495
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.74250.32541420.31272697X-RAY DIFFRACTION100
1.7425-1.78970.33491450.27962741X-RAY DIFFRACTION100
1.7897-1.84230.28291410.26852675X-RAY DIFFRACTION100
1.8423-1.90180.41591300.34532468X-RAY DIFFRACTION91
1.9018-1.96980.45821400.41732657X-RAY DIFFRACTION97
1.9698-2.04860.24831440.23112717X-RAY DIFFRACTION100
2.0486-2.14190.24611430.19762722X-RAY DIFFRACTION100
2.1419-2.25480.29531370.27762594X-RAY DIFFRACTION94
2.2548-2.3960.27811400.22762669X-RAY DIFFRACTION97
2.396-2.5810.2431440.19532738X-RAY DIFFRACTION100
2.581-2.84080.21271450.192761X-RAY DIFFRACTION100
2.8408-3.25180.241470.20262777X-RAY DIFFRACTION100
3.2518-4.09660.20671480.16782812X-RAY DIFFRACTION100
4.0966-49.27740.18161540.16282924X-RAY DIFFRACTION100
Refinement TLS params.

S33: 0 Å ° / 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 °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.83010.23910.0391.23490.6040.9695-0.03980.00490.01450.0024-0.01280.3159-0.2662-0.25580.25530.05430.02710.24810.00050.2585-31.1075-4.923519.1214
21.47360.358-0.00760.6631-0.18940.75640.0255-0.01630.16290.0722-0.01860.0083-0.2176-0.02120.24250.0289-0.01110.1851-0.00610.1933-8.3579-1.640221.2993
31.31160.14550.0150.7929-0.10990.54470.03270.1034-0.02320.043-0.0236-0.1066-0.05830.07920.21860.0171-0.01130.1769-0.01950.1752-0.6156-5.853515.3381
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 5 through 102 )
2X-RAY DIFFRACTION2chain 'A' and (resid 103 through 201 )
3X-RAY DIFFRACTION3chain 'A' and (resid 202 through 352 )

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