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- PDB-9cj5: Unphosphorylated human p38 alpha bound to pexmetinib -

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Basic information

Entry
Database: PDB / ID: 9cj5
TitleUnphosphorylated human p38 alpha bound to pexmetinib
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / MAPK14 / kinase / inhibitor
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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / 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 / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / 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
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
: / 1,3-PROPANDIOL / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsStadnicki, E.J. / Ludewig, H. / Prem Kumar, R. / Kern, D. / Bradshaw, N.
Funding support United States, 2items
OrganizationGrant numberCountry
Other private United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Biorxiv / Year: 2024
Title: Dual-Action Kinase Inhibitors Influence p38 alpha MAP Kinase Dephosphorylation.
Authors: Stadnicki, E.J. / Ludewig, H. / Kumar, R.P. / Wang, X. / Qiao, Y. / Kern, D. / Bradshaw, N.
History
DepositionJul 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,2247
Polymers41,3431
Non-polymers8816
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.855, 44.855, 215.906
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID- ...MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-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: 41343.195 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 BL21 (bacteria)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-A1AWV / Pexmetinib / N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-[(5-fluoro-2-{[1-(2-hydroxyethyl)-1H-indazol-5-yl]oxy}phenyl)methyl]urea


Mass: 556.631 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H33FN6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PDO / 1,3-PROPANDIOL


Mass: 76.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2
Has ligand of interestY
Has protein modificationN

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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: 2.63 Å3/Da / Density % sol: 53.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 8mg/mL p38 alpha incubated with 250uM pexmetinib with a final DMSO concentration of 5% set at a 1:1 ratio with 100 mM MES pH 6.0, 200 mM ammonium sulfate, 4% 1,3-Propanediol, and 20% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Nov 18, 2023
RadiationMonochromator: Double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→44.85 Å / Num. obs: 6362 / % possible obs: 99.48 % / Redundancy: 13.9 % / Biso Wilson estimate: 130.42 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.222 / Rpim(I) all: 0.087 / Rrim(I) all: 0.23 / Net I/σ(I): 10.6
Reflection shellResolution: 3.3→3.56 Å / Mean I/σ(I) obs: 0.7 / Num. unique obs: 3175 / CC1/2: 0.362 / % possible all: 99.25

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.3→31.72 Å / SU ML: 0 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 42.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2755 307 4.83 %
Rwork0.2458 --
obs0.2472 6362 99.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.3→31.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2697 0 62 0 2759
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032817
X-RAY DIFFRACTIONf_angle_d0.5763807
X-RAY DIFFRACTIONf_dihedral_angle_d11.9381044
X-RAY DIFFRACTIONf_chiral_restr0.039424
X-RAY DIFFRACTIONf_plane_restr0.005476
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-4.160.40681540.37173021X-RAY DIFFRACTION99
4.16-31.720.24081530.2083034X-RAY DIFFRACTION100
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)
18.5203-4.76562.40387.48184.07998.96750.53790.2402-0.46741.6422-0.8988-0.56940.20981.27170.21611.6916-0.321-0.19871.5050.41911.3298-9.1758-18.609112.5553
20.6553-1.9734-1.86187.7166-0.59958.16360.57330.5486-0.93860.4475-0.04670.25291.45950.0806-0.59041.733-0.0191-0.52011.17240.07061.4696-3.8188-23.48871.1498
38.62155.128-3.01938.3562-4.27869.75270.64870.0598-0.31140.5533-0.142-0.35930.11331.3119-0.55531.1460.3392-0.24871.1486-0.16671.04674.1208-14.4329-4.1608
45.64761.37795.38854.7743-5.10677.62970.21340.9078-0.0369-0.260.29660.51580.1436-0.449-0.65861.07630.1770.09731.4211-0.03241.0152-3.3006-7.3437-23.536
51.71890.5371-1.01143.3499-3.13998.7380.53130.538-1.0844-0.37030.0026-0.47631.69921.3164-0.48411.52320.4195-0.24631.5638-0.22171.69685.8754-17.9865-15.6267
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 5 through 35 )
2X-RAY DIFFRACTION2chain 'A' and (resid 37 through 90 )
3X-RAY DIFFRACTION3chain 'A' and (resid 91 through 166 )
4X-RAY DIFFRACTION4chain 'A' and (resid 167 through 261 )
5X-RAY DIFFRACTION5chain 'A' and (resid 262 through 352 )

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