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- PDB-9r25: Sorafenib in complex with p38alpha (MAPK14) -

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Basic information

Entry
Database: PDB / ID: 9r25
TitleSorafenib in complex with p38alpha (MAPK14)
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / Kinase / Inhibitor / Approved / Matched Molecular Pair / MMP
Function / homology
Function and homology information


Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / CD163 mediating an anti-inflammatory response / positive regulation of cyclase activity / response to dietary excess ...Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / CD163 mediating an anti-inflammatory response / positive regulation of cyclase activity / response to dietary excess / positive regulation of myotube differentiation / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of muscle cell differentiation / cellular response to UV-B / mitogen-activated protein kinase p38 binding / Myogenesis / Platelet sensitization by LDL / NFAT protein binding / cellular response to lipoteichoic acid / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / cellular response to vascular endothelial growth factor stimulus / MAP kinase activity / mitogen-activated protein kinase / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / RHO GTPases Activate NADPH Oxidases / negative regulation of hippo signaling / positive regulation of myoblast differentiation / osteoclast differentiation / positive regulation of interleukin-12 production / signal transduction in response to DNA damage / p38MAPK events / positive regulation of erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / cellular response to virus / activated TAK1 mediates p38 MAPK activation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / platelet activation / bone development / response to insulin / NOD1/2 Signaling Pathway / cellular senescence / VEGFA-VEGFR2 Pathway / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / chemotaxis / spindle pole / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / MAPK cascade / ADP signalling through P2Y purinoceptor 1 / cellular response to lipopolysaccharide / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / cell surface receptor signaling pathway / nuclear speck / intracellular signal transduction / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / positive regulation of gene expression / regulation of transcription by RNA polymerase II / Neutrophil degranulation / glutamatergic synapse / enzyme binding / signal transduction / mitochondrion / DNA-templated transcription / extracellular region / 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-BAX / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsGomez, S.M. / Buehrmann, M. / Klein, A. / Vasa, S.K. / Weisner, J. / Vatheuer, H. / Czodrowski, P. / Rauh, D. / Linser, R.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: To Be Published
Title: Sorafenib and regorafenib differentially impact the dynamic conformational ensemble of p38alpha
Authors: Gomez, S.M. / Buehrmann, M. / Klein, A. / Vasa, S.K. / Weisner, J. / Vatheuer, H. / Czodrowski, P. / Rauh, D. / Linser, R.
History
DepositionApr 29, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 6, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,1003
Polymers41,3431
Non-polymers7572
Water3,981221
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint2 kcal/mol
Surface area16580 Å2
Unit cell
Length a, b, c (Å)66.430, 75.080, 78.340
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 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / ...MAPK 14 / Cytokine suppressive anti-inflammatory drug-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 (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-BAX / 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE / Sorafenib


Mass: 464.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16ClF3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / 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: 2.36 Å3/Da / Density % sol: 47.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, 21-29 % PEG4000, 25 mM BOG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.977956 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977956 Å / Relative weight: 1
ReflectionResolution: 1.8→42 Å / Num. obs: 476611 / % possible obs: 100 % / Redundancy: 12.88 % / Biso Wilson estimate: 33.39 Å2 / CC1/2: 0.99 / Net I/σ(I): 23.38
Reflection shellResolution: 1.8→1.9 Å / Num. unique obs: 37001 / CC1/2: 0.79

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→42 Å / SU ML: 0.2229 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.3962
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2099 1850 5 %
Rwork0.1812 35147 -
obs0.1827 36997 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.51 Å2
Refinement stepCycle: LAST / Resolution: 1.8→42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2664 0 52 221 2937
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01182790
X-RAY DIFFRACTIONf_angle_d1.13973792
X-RAY DIFFRACTIONf_chiral_restr0.0698427
X-RAY DIFFRACTIONf_plane_restr0.0098481
X-RAY DIFFRACTIONf_dihedral_angle_d14.59951025
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.29171400.25862670X-RAY DIFFRACTION100
1.85-1.90.30831410.24212673X-RAY DIFFRACTION100
1.9-1.960.28691390.25672653X-RAY DIFFRACTION99.89
1.96-2.030.27291400.21952647X-RAY DIFFRACTION100
2.03-2.120.24231420.18532695X-RAY DIFFRACTION99.96
2.12-2.210.25421400.19382664X-RAY DIFFRACTION99.96
2.21-2.330.2451410.19242677X-RAY DIFFRACTION99.93
2.33-2.480.21911410.19622690X-RAY DIFFRACTION100
2.48-2.670.28181420.19792702X-RAY DIFFRACTION100
2.67-2.930.22361440.20242723X-RAY DIFFRACTION99.97
2.93-3.360.18991430.19012713X-RAY DIFFRACTION100
3.36-4.230.1971450.15372756X-RAY DIFFRACTION100
4.23-420.16561520.162884X-RAY DIFFRACTION99.9
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)
14.58531680654-0.2542029395810.5614497537923.27023246257-1.210309450993.211519228340.0196830835090.21842237319-0.0124652412636-0.3075741361730.0984572447770.6065573716780.149581186985-0.48943016694-0.1069771781030.297349323972-0.00481020508048-0.01011119096560.263449260394-0.01449127257740.290107810129-12.6962222923-2.37395417971-15.156594883
24.49585267834-0.177136845093-0.9086612303651.059834903450.7043893451521.38796942519-0.01997491030860.2801238738390.00767318654363-0.121015337717-0.01221453686630.102421352997-0.0004462135321890.0753177825888-0.01459653207540.298887179305-0.0154917007884-0.02830101265490.2031718071280.04204614269920.1762158756639.68109363262-0.788962720368-18.6310459532
32.720917870480.0660302038919-0.586882245991.35877615991-0.2031210499981.212063572860.0225601543511-0.0713431100585-0.0920870445018-0.0304067982639-0.0911622115428-0.2345754433290.02893908606820.2424311517430.06841808690060.287493944084-0.0191624927025-0.03547287300470.2200639787780.05026842898030.18959786461317.4035671803-5.71984709243-14.485270884
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 5 through 102 )5 - 1021 - 95
22chain 'A' and (resid 103 through 201 )103 - 20196 - 179
33chain 'A' and (resid 202 through 353 )202 - 353180 - 331

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