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- PDB-7pvu: Crystal structure of p38alpha C162S in complex with CAS2094511-69... -

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Entry
Database: PDB / ID: 7pvu
TitleCrystal structure of p38alpha C162S in complex with CAS2094511-69-8, P 1 21 1
ComponentsMitogen-activated protein kinase 14
KeywordsONCOPROTEIN / kinase / enzyme / inhibitor / ligand
Function / homology
Function and homology information


p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / Regulation of TP53 Activity through Phosphorylation / Myogenesis / VEGFA-VEGFR2 Pathway / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / 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 / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / positive regulation of interleukin-12 production / Neutrophil degranulation / osteoclast differentiation / positive regulation of erythrocyte 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 / stem cell differentiation / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cellular response to virus / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / spindle pole / osteoblast differentiation / kinase activity / cellular response to tumor necrosis factor / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / protein phosphatase binding / response to lipopolysaccharide / transcription by RNA polymerase II / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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-8DI / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.154 Å
AuthorsBaginski, B. / Pous, J. / Gonzalez, L. / Macias, M.J. / Nebreda, A.R.
Funding support Spain, 2items
OrganizationGrant numberCountry
Spanish Ministry of Science, Innovation, and UniversitiesPID2019-109521RB-100 Spain
La Caixa FoundationBioMedTec VIII - Nebre Spain
CitationJournal: Nat Commun / Year: 2023
Title: Characterization of p38 alpha autophosphorylation inhibitors that target the non-canonical activation pathway.
Authors: Gonzalez, L. / Diaz, L. / Pous, J. / Baginski, B. / Duran-Corbera, A. / Scarpa, M. / Brun-Heath, I. / Igea, A. / Martin-Malpartida, P. / Ruiz, L. / Pallara, C. / Esguerra, M. / Colizzi, F. / ...Authors: Gonzalez, L. / Diaz, L. / Pous, J. / Baginski, B. / Duran-Corbera, A. / Scarpa, M. / Brun-Heath, I. / Igea, A. / Martin-Malpartida, P. / Ruiz, L. / Pallara, C. / Esguerra, M. / Colizzi, F. / Mayor-Ruiz, C. / Biondi, R.M. / Soliva, R. / Macias, M.J. / Orozco, M. / Nebreda, A.R.
History
DepositionOct 5, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _citation.year
Revision 1.2Jun 21, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 14
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,8153
Polymers82,4702
Non-polymers3451
Water3,351186
1
A: Mitogen-activated protein kinase 14


Theoretical massNumber of molelcules
Total (without water)41,2351
Polymers41,2351
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5802
Polymers41,2351
Non-polymers3451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.141, 68.072, 79.980
Angle α, β, γ (deg.)90.000, 94.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 41235.020 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical ChemComp-8DI / N-(2-cyclobutyl-1H-1,3-benzodiazol-5-yl)-2-fluorobenzene-1-sulfonamide / N-(2-cyclobutyl-1H-benzimidazol-5-yl)-2-fluoranyl-benzenesulfonamide


Mass: 345.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16FN3O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.3 Å3/Da / Density % sol: 46.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8 / Details: 27% PEG 3350, 0,1M BIS-TRIS pH 6.8 / Temp details: RT

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Oxford Cryosystems 700 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 24, 2020 / Details: Eliptically bent mirror
RadiationMonochromator: Si(111) channel-cut, cryocooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 1.82→79.702 Å / Num. obs: 44958 / % possible obs: 100 % / Redundancy: 5.8 % / Biso Wilson estimate: 26.7 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 16
Reflection shellResolution: 1.82→1.92 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.453 / Mean I/σ(I) obs: 4.4 / Num. unique obs: 4938 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
MOSFLM7.3.0data reduction
SCALA3.3.22data scaling
PDB_EXTRACT3.27data extraction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3que

3que


Resolution: 2.154→79.702 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.941 / WRfactor Rfree: 0.284 / WRfactor Rwork: 0.224 / SU B: 12.974 / SU ML: 0.163 / Average fsc free: 0.9551 / Average fsc work: 0.9687 / Cross valid method: THROUGHOUT / ESU R: 0.283 / ESU R Free: 0.206
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2395 2015 5.191 %
Rwork0.2053 36801 -
all0.207 --
obs-38816 99.286 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 56.897 Å2
Baniso -1Baniso -2Baniso -3
1--0.182 Å20 Å20.263 Å2
2---1.308 Å2-0 Å2
3---1.426 Å2
Refinement stepCycle: LAST / Resolution: 2.154→79.702 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5435 0 24 186 5645
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0125566
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165321
X-RAY DIFFRACTIONr_angle_refined_deg0.9341.6557560
X-RAY DIFFRACTIONr_angle_other_deg0.3191.5812242
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4745666
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.117537
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.90710965
X-RAY DIFFRACTIONr_dihedral_angle_6_deg12.58710262
X-RAY DIFFRACTIONr_chiral_restr0.0410.2845
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026423
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021281
X-RAY DIFFRACTIONr_nbd_refined0.1890.21110
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1830.24938
X-RAY DIFFRACTIONr_nbtor_refined0.1720.22736
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0740.22742
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2174
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1660.215
X-RAY DIFFRACTIONr_nbd_other0.1720.259
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2080.28
X-RAY DIFFRACTIONr_mcbond_it1.6423.7342670
X-RAY DIFFRACTIONr_mcbond_other1.6423.7342670
X-RAY DIFFRACTIONr_mcangle_it2.9196.73328
X-RAY DIFFRACTIONr_mcangle_other2.9186.7013329
X-RAY DIFFRACTIONr_scbond_it1.4533.922896
X-RAY DIFFRACTIONr_scbond_other1.4533.9212897
X-RAY DIFFRACTIONr_scangle_it2.5937.1324228
X-RAY DIFFRACTIONr_scangle_other2.5937.1344229
X-RAY DIFFRACTIONr_lrange_it5.48837.5246228
X-RAY DIFFRACTIONr_lrange_other5.46436.9366203
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.154-2.210.3241550.26225610.26528620.9360.95394.89870.244
2.21-2.270.3331810.28326290.28628200.9220.94399.64540.264
2.27-2.3360.2761580.24925530.2527190.9560.96299.70580.232
2.336-2.4080.2811360.22724930.2326380.9460.96899.65880.214
2.408-2.4870.291320.22324370.22725770.9530.9799.68960.209
2.487-2.5740.2711190.22423450.22624720.9560.9799.67640.214
2.574-2.6710.2471110.21722840.21924100.9590.9799.37760.21
2.671-2.780.2741140.21921730.22223000.9410.97199.43480.218
2.78-2.9030.2691300.22220800.22522200.9540.9799.54960.223
2.903-3.0450.263930.21920140.22121120.9610.9799.76330.225
3.045-3.2090.281870.22219370.22520270.9530.9799.8520.234
3.209-3.4040.237940.2117950.21218940.9720.97399.7360.226
3.404-3.6380.205800.20417060.20417920.9750.97699.66520.221
3.638-3.9290.24530.18816270.1916860.9670.97899.64410.213
3.929-4.3030.217870.17314480.17515400.9760.98299.67530.206
4.303-4.8090.1991060.17713110.17914230.9790.98199.57840.219
4.809-5.550.177650.18111710.18112410.9830.98399.59710.219
5.55-6.7890.278490.21310030.21610590.9650.97699.3390.264
6.789-9.5660.212330.1777890.1788260.9680.98199.51570.226
9.566-79.7020.234320.2084450.2094770.9610.9751000.265
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)
10.880.7432-0.25893.431-0.89420.49720.0975-0.144-0.00360.2872-0.126-0.2713-0.08420.09880.02850.0312-0.0124-0.02780.0404-0.01540.045314.333437.83553.9162
22.17920.04030.31032.74581.56022.18680.198-0.1675-0.09260.0514-0.1210.21250.1551-0.1747-0.0770.1249-0.02540.04020.3153-0.03810.091516.260924.958446.1319
Refinement TLS groupSelection: ALL

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