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- PDB-7z6i: Crystal structure of p38alpha C162S in complex with SB20358 and C... -

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Basic information

Entry
Database: PDB / ID: 7z6i
TitleCrystal structure of p38alpha C162S in complex with SB20358 and CAS 2094667-81-7 (behind catalytic site; Y35 in), P 21 21 21
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. / : / 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-87B / Chem-IIM / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 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
DepositionMar 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 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 1.2Feb 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
AAA: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0683
Polymers41,3631
Non-polymers7052
Water3,603200
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16800 Å2
Unit cell
Length a, b, c (Å)65.142, 74.570, 77.550
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 / MAP kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 41363.148 Da / Num. of mol.: 1 / Mutation: C162S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical ChemComp-IIM / 4-[4-(4-fluorophenyl)-2-[4-[methyl(oxidanyl)-$l^{3}-sulfanyl]phenyl]-1~{H}-imidazol-5-yl]pyridine


Mass: 377.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16FN3OS
#3: Chemical ChemComp-87B / N-(2-cyclobutyl-1H-1,3-benzodiazol-5-yl)benzenesulfonamide


Mass: 327.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N3O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / 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: 2.35 Å3/Da / Density % sol: 47.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 0.087 M Ca Acetate 0.1M MES pH 6.0 7.1% PEG 550MME

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: oxford Cryo 700 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2020 / Details: Elliptically bent mirror
RadiationMonochromator: Si(111) channel-cut, cryocooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.25→77.55 Å / Num. obs: 18525 / % possible obs: 100 % / Redundancy: 5.6 % / Biso Wilson estimate: 28.9 Å2 / Rmerge(I) obs: 0.092 / Net I/σ(I): 16.5
Reflection shellResolution: 2.25→2.37 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.451 / Mean I/σ(I) obs: 9.2 / Num. unique obs: 2625 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0403refinement
autoPROC1.0.5data reduction
SCALA3.3.22data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LOO

4loo


Resolution: 2.25→53.752 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.914 / WRfactor Rfree: 0.267 / WRfactor Rwork: 0.211 / SU B: 6.485 / SU ML: 0.164 / Average fsc free: 0.9574 / Average fsc work: 0.9748 / Cross valid method: FREE R-VALUE / ESU R: 0.318 / ESU R Free: 0.233
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2479 884 4.784 %random
Rwork0.1929 17596 --
all0.195 ---
obs-18480 99.957 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 36.604 Å2
Baniso -1Baniso -2Baniso -3
1--0.918 Å2-0 Å2-0 Å2
2---1.492 Å20 Å2
3---2.409 Å2
Refinement stepCycle: LAST / Resolution: 2.25→53.752 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2824 0 50 200 3074
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0122843
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162685
X-RAY DIFFRACTIONr_angle_refined_deg1.1821.6593872
X-RAY DIFFRACTIONr_angle_other_deg0.4091.5836161
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7215343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.757520
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.39910472
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.86710134
X-RAY DIFFRACTIONr_chiral_restr0.0480.2427
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023316
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02675
X-RAY DIFFRACTIONr_nbd_refined0.2140.2567
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2070.22472
X-RAY DIFFRACTIONr_nbtor_refined0.180.21402
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0770.21411
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1610.2159
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.050.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1460.211
X-RAY DIFFRACTIONr_nbd_other0.1780.242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.160.23
X-RAY DIFFRACTIONr_mcbond_it2.2573.9951349
X-RAY DIFFRACTIONr_mcbond_other2.2553.9961349
X-RAY DIFFRACTIONr_mcangle_it3.8137.1671684
X-RAY DIFFRACTIONr_mcangle_other3.8127.1691685
X-RAY DIFFRACTIONr_scbond_it2.3044.2571494
X-RAY DIFFRACTIONr_scbond_other2.3044.2591495
X-RAY DIFFRACTIONr_scangle_it3.9687.7082181
X-RAY DIFFRACTIONr_scangle_other3.9677.712182
X-RAY DIFFRACTIONr_lrange_it6.40540.0673281
X-RAY DIFFRACTIONr_lrange_other6.32939.8773246
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
2.25-2.3080.276600.20912580.21313190.9520.9799.92420.193
2.308-2.3710.244670.21412320.21612990.9590.9671000.203
2.371-2.440.272670.20912070.21312740.9420.971000.199
2.44-2.5150.294560.2111960.21412520.9430.9691000.204
2.515-2.5970.244740.20311260.20512000.9560.9741000.201
2.597-2.6880.289550.211060.20411640.9490.97499.74230.201
2.688-2.7890.26600.18210510.18511110.9560.9781000.181
2.789-2.9030.252450.17510550.17811010.9690.9899.90920.182
2.903-3.0320.235460.189820.18210280.9660.9781000.189
3.032-3.1790.24410.1859630.18610040.9650.9771000.198
3.179-3.3510.211460.1899070.199530.9710.9771000.204
3.351-3.5530.262420.1998710.2029130.9480.9741000.222
3.553-3.7970.267460.1768050.188510.960.9811000.2
3.797-4.10.223340.1687710.178060.970.98299.87590.201
4.1-4.4880.268320.1677070.177390.9660.9821000.202
4.488-5.0140.238240.1736520.1756770.9570.98199.85230.216
5.014-5.7810.164230.2255760.2225990.9830.9721000.269
5.781-7.060.306270.2284960.2325230.9410.9711000.284
7.06-9.8990.262190.1883960.1914160.9520.97899.75960.247
9.899-53.7520.214200.2842390.2782590.9780.951000.353

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