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- PDB-8vxe: Structure of p38 alpha (Mitogen-activated protein kinase 14) comp... -

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Basic information

Entry
Database: PDB / ID: 8vxe
TitleStructure of p38 alpha (Mitogen-activated protein kinase 14) complexed with inhibitor 6
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / TRANSFERASE / p38 alpha / MAPK14 / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / 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 / DSCAM interactions ...positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / 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 / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to dietary excess / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / signal transduction in response to DNA damage / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / negative regulation of inflammatory response to antigenic stimulus / 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 / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / placenta development / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / platelet activation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / Regulation of TP53 Activity through Phosphorylation / cellular response to lipopolysaccharide / 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 / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsBlaesse, M. / Steinbacher, S. / Shaffer, P.L. / Sharma, S. / Thompson, A.A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Structure-Based Optimization of Selective and Brain Penetrant CK1 delta Inhibitors for the Treatment of Circadian Disruptions.
Authors: McCarver, S. / Hanna, L. / Samant, A. / Thompson, A.A. / Seierstad, M. / Saha, A. / Wu, D. / Lord, B. / Sutton, S.W. / Shah, V. / Milligan, C.M. / Wennerholm, M. / Shelton, J. / Lebold, T.P. / Shireman, B.T.
History
DepositionFeb 4, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 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)45,2423
Polymers44,6581
Non-polymers5852
Water2,720151
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.124, 74.341, 78.029
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 / MAPK14 / 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: 44657.684 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(DE3) (bacteria)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-A1AD9 / (4M)-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine


Mass: 292.310 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H13FN4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.15 Å3/Da / Density % sol: 42.72 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5 / Details: 10% PEG6000, 0.1 MES/NaOH pH 5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 1.85→49.46 Å / Num. obs: 32652 / % possible obs: 97.4 % / Redundancy: 3.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.028 / Rrim(I) all: 0.033 / Net I/σ(I): 24.04
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.85-2.10.46100060.9320.5341
2.1-2.590.096103830.9930.1121
2.59-3.280.02661900.9990.031
3.28-4.220.01831640.9990.0221
4.22-6.150.01719560.9990.021
6.15-9.850.027220.9980.0251
9.85-49.460.0232310.9970.0291

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0232refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→49.46 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.924 / SU B: 5.801 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.165 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28853 2236 7 %RANDOM
Rwork0.2179 ---
obs0.2228 29677 95.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.929 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å2-0 Å2-0 Å2
2---2.35 Å20 Å2
3---2.24 Å2
Refinement stepCycle: LAST / Resolution: 1.85→49.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2653 0 44 151 2848
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132745
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172558
X-RAY DIFFRACTIONr_angle_refined_deg1.3591.6653733
X-RAY DIFFRACTIONr_angle_other_deg0.4491.5865916
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3425326
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.93122.555137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.18615461
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.191515
X-RAY DIFFRACTIONr_chiral_restr0.0590.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023024
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02573
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it9.0556.3421313
X-RAY DIFFRACTIONr_mcbond_other9.0226.3421312
X-RAY DIFFRACTIONr_mcangle_it10.74810.6481636
X-RAY DIFFRACTIONr_mcangle_other10.75810.651637
X-RAY DIFFRACTIONr_scbond_it10.397.0141432
X-RAY DIFFRACTIONr_scbond_other10.3867.0131433
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.67411.4812098
X-RAY DIFFRACTIONr_long_range_B_refined13.62156.7323113
X-RAY DIFFRACTIONr_long_range_B_other13.63956.6483092
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.462 162 -
Rwork0.463 2012 -
obs--89.03 %

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