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- PDB-3heg: P38 in complex with Sorafenib -

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Basic information

Entry
Database: PDB / ID: 3heg
TitleP38 in complex with Sorafenib
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / Transferases / ATP-binding / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / 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 / cartilage condensation ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / 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 / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / 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 / positive regulation of D-glucose import / stem cell differentiation / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / NOD1/2 Signaling Pathway / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / ADP signalling through P2Y purinoceptor 1 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / secretory granule lumen / 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 / glutamatergic synapse / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
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: 2.2 Å
AuthorsNamboodiri, H.V. / Karpusas, M.
CitationJournal: Biochemistry / Year: 2010
Title: Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases.
Authors: Namboodiri, H.V. / Bukhtiyarova, M. / Ramcharan, J. / Karpusas, M. / Lee, Y. / Springman, E.B.
History
DepositionMay 8, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)40,3712
Polymers39,9061
Non-polymers4651
Water1,964109
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.492, 74.249, 77.843
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 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti- ...Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2 / SAPK2A


Mass: 39905.695 Da / Num. of mol.: 1 / Fragment: Kinase Domain, UNP residues 5-352
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta
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 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O

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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: 2.37 Å3/Da / Density % sol: 48.13 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 10-20% PEG 4000, 0.1 M Cacodylic acid, 50 mM n-octyl-beta-D-glucoside, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 11, 2005 / Details: Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.2→40 Å / Num. obs: 19920 / % possible obs: 99 % / Rmerge(I) obs: 0.86 / Rsym value: 0.64 / Net I/σ(I): 20
Reflection shellResolution: 2.2→2.37 Å / Rmerge(I) obs: 0.559 / Mean I/σ(I) obs: 2.2 / Num. unique all: 3893 / Rsym value: 0.521 / % possible all: 99.8

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1ZYJ

1zyj


Resolution: 2.2→40 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.889 / SU B: 8.475 / SU ML: 0.218 / Cross valid method: THROUGHOUT / ESU R: 0.329 / ESU R Free: 0.27 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.30929 1008 5.1 %RANDOM
Rwork0.23635 ---
obs0.24004 18776 99.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.069 Å2
Baniso -1Baniso -2Baniso -3
1--0.62 Å20 Å20 Å2
2---1.42 Å20 Å2
3---2.04 Å2
Refinement stepCycle: LAST / Resolution: 2.2→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2687 0 32 109 2828
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222802
X-RAY DIFFRACTIONr_angle_refined_deg1.7141.9773807
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.775334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.30123.817131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.00715486
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5881519
X-RAY DIFFRACTIONr_chiral_restr0.1220.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022115
X-RAY DIFFRACTIONr_nbd_refined0.2320.21319
X-RAY DIFFRACTIONr_nbtor_refined0.3150.21862
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1890.2117
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2680.234
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2650.24
X-RAY DIFFRACTIONr_mcbond_it0.9171.51722
X-RAY DIFFRACTIONr_mcangle_it1.58122713
X-RAY DIFFRACTIONr_scbond_it2.08431241
X-RAY DIFFRACTIONr_scangle_it3.0454.51092
LS refinement shellResolution: 2.2→2.255 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 61 -
Rwork0.282 1350 -
obs--96.58 %

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