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- PDB-9d7n: Human p38alpha MAP Kinase in complex with 1-Isobutyl-1H-indazole ... -

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Basic information

Entry
Database: PDB / ID: 9d7n
TitleHuman p38alpha MAP Kinase in complex with 1-Isobutyl-1H-indazole derivative; OSF267
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / P38 / KINASE / INHIBITOR / COMPLEX
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 / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / D-glucose import / p38MAPK cascade / ERK/MAPK targets / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / signal transduction in response to DNA damage / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / 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 / p38MAPK events / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / positive regulation of interleukin-12 production / positive regulation of erythrocyte differentiation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / response to insulin / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / chemotaxis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / 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 / 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 / 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
: / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.973 Å
AuthorsBrunzelle, J.S. / Shuvalova, L. / Benetik, S.F. / Roy, S.M. / Watterson, D.M. / Gobec, S.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2025
Title: Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38 alpha Mitogen-Activated Protein Kinase Inhibitors.
Authors: Ferjancic Benetik, S. / Proj, M. / Knez, D. / Kosak, U. / Meden, A. / Krajsek, K. / Pislar, A. / Horvat, S. / Svajger, U. / Tesic, N. / Pulkrabkova, L. / Soukup, O. / Skarka, A. / Andrys, R. ...Authors: Ferjancic Benetik, S. / Proj, M. / Knez, D. / Kosak, U. / Meden, A. / Krajsek, K. / Pislar, A. / Horvat, S. / Svajger, U. / Tesic, N. / Pulkrabkova, L. / Soukup, O. / Skarka, A. / Andrys, R. / Brazzolotto, X. / Igert, A. / Nachon, F. / Dias, J. / Detka, J. / Gdula-Argasinska, J. / Wyska, E. / Szafarz, M. / Manik, A. / Plachtij, N. / Musilek, K. / Salat, K. / Obreza, A. / Gobec, S.
History
DepositionAug 16, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 2025Provider: 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)40,4383
Polymers39,7851
Non-polymers6542
Water1,45981
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.392, 75.381, 79.241
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 39784.582 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: Chemical ChemComp-A1A2O / 5-[(2,4-difluorophenyl)methyl]-N-[2-(dimethylamino)ethyl]-1-(2-methylpropyl)-1H-indazole-6-carboxamide


Mass: 414.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28F2N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GG5 / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE


Mass: 239.248 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10FN3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / Source method: isolated from a natural source / Formula: H2O
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: 2.49 Å3/Da / Density % sol: 50.64 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M Ammonium Acetate, 0.1M BisTris (pH 5.5), 20% PEG 10,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.8731 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Jul 14, 2023 / Details: Vertical CRL / Horizontal Eliptical mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 1.973→54.616 Å / Num. obs: 23225 / % possible obs: 90 % / Redundancy: 13.9 % / Biso Wilson estimate: 37.97 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.034 / Rrim(I) all: 0.127 / Net I/σ(I): 12.6
Reflection shellResolution: 1.973→2.233 Å / Redundancy: 13.8 % / Rmerge(I) obs: 1.668 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 879 / CC1/2: 0.662 / Rpim(I) all: 0.468 / Rrim(I) all: 1.733 / % possible all: 60.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROC1.1.7data reduction
Aimless0.7.7data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.973→54.616 Å / SU ML: 0.2126 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.6912
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2573 864 4.92 %
Rwork0.2118 16701 -
obs0.214 17565 61.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.64 Å2
Refinement stepCycle: LAST / Resolution: 1.973→54.616 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2721 0 48 81 2850
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00262878
X-RAY DIFFRACTIONf_angle_d0.59983914
X-RAY DIFFRACTIONf_chiral_restr0.0403429
X-RAY DIFFRACTIONf_plane_restr0.0046510
X-RAY DIFFRACTIONf_dihedral_angle_d5.638403
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.973-2.10.599970.3423131X-RAY DIFFRACTION2.93
2.1-2.260.3654460.2914822X-RAY DIFFRACTION18.55
2.26-2.490.3471440.29052721X-RAY DIFFRACTION60.74
2.49-2.850.28742120.26584120X-RAY DIFFRACTION91.16
2.85-3.580.2662240.22764424X-RAY DIFFRACTION96.71
3.58-54.6160.22792310.17614483X-RAY DIFFRACTION94.72
Refinement TLS params.Method: refined / Origin x: 6.466939339 Å / Origin y: 3.96979149243 Å / Origin z: 16.0411186872 Å
111213212223313233
T0.0539786599954 Å20.0449946012911 Å20.00746125986405 Å2--0.0439963977417 Å20.175050863513 Å2---0.166236247024 Å2
L0.92382419423 °2-0.174404177059 °2-0.138558484455 °2-2.05117130328 °2-0.192694755525 °2--1.19364801311 °2
S0.205028493328 Å °-0.00400979647894 Å °-0.225341560799 Å °0.29293650569 Å °-0.249852589154 Å °0.445404074775 Å °-0.01305842928 Å °-0.04178927197 Å °-0.747455674848 Å °
Refinement TLS groupSelection details: all

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