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- PDB-5mz3: P38 ALPHA MUTANT C162S IN COMPLEX WITH CMPD2 [N-(4-Methyl-3-(4,4,... -

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Basic information

Entry
Database: PDB / ID: 5mz3
TitleP38 ALPHA MUTANT C162S IN COMPLEX WITH CMPD2 [N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide]
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / kinase / inhibitor / phosphotransferase
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 / cartilage condensation ...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 / cartilage condensation / DSCAM interactions / 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 / regulation of cytokine production involved in inflammatory response / ERK/MAPK targets / 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 / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / signal transduction in response to DNA damage / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / 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 / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / placenta development / 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 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / 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 / 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. / 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 ...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-8EN / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsCowan-Jacob, S.W. / Scheufler, C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.
Authors: Smith, A. / Ni, Z.J. / Poon, D. / Huang, Z. / Chen, Z. / Zhang, Q. / Tandeske, L. / Merritt, H. / Shoemaker, K. / Chan, J. / Kaufman, S. / Huh, K. / Murray, J. / Appleton, B.A. / Cowan- ...Authors: Smith, A. / Ni, Z.J. / Poon, D. / Huang, Z. / Chen, Z. / Zhang, Q. / Tandeske, L. / Merritt, H. / Shoemaker, K. / Chan, J. / Kaufman, S. / Huh, K. / Murray, J. / Appleton, B.A. / Cowan-Jacob, S.W. / Scheufler, C. / Kanazawa, T. / Jansen, J.M. / Stuart, D. / Shafer, C.M.
History
DepositionJan 30, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 15, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 7, 2018Group: Data collection / Source and taxonomy / Structure summary
Category: entity / entity_src_gen / entity_src_nat / Item: _entity.src_method
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)42,8982
Polymers42,4451
Non-polymers4521
Water5,026279
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.919, 85.607, 127.468
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 / 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: 42445.359 Da / Num. of mol.: 1 / Mutation: C162S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-8EN / ~{N}-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methyl-phenyl]-3-(trifluoromethyl)benzamide


Mass: 452.428 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H19F3N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.95 Å3/Da / Density % sol: 58.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 19% PEG8000, 20mM Mg acetate and 0.1M Hepes pH7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.0063 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 31, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0063 Å / Relative weight: 1
ReflectionResolution: 2.15→26.34 Å / Num. obs: 28075 / % possible obs: 99.8 % / Redundancy: 4.78 % / Biso Wilson estimate: 32.15 Å2 / Rmerge(I) obs: 0.083 / Net I/σ(I): 16.3
Reflection shellResolution: 2.15→2.22 Å / Redundancy: 4.86 % / Rmerge(I) obs: 0.476 / Mean I/σ(I) obs: 3.51 / % possible all: 99.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
BUSTER2.11.7refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→26.34 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.935 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.171 / SU Rfree Blow DPI: 0.146 / SU Rfree Cruickshank DPI: 0.141
RfactorNum. reflection% reflectionSelection details
Rfree0.197 1404 5 %RANDOM
Rwork0.165 ---
obs0.166 28075 99.9 %-
Displacement parametersBiso mean: 34.79 Å2
Baniso -1Baniso -2Baniso -3
1--1.4134 Å20 Å20 Å2
2---0.9719 Å20 Å2
3---2.3854 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 2.15→26.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2793 0 33 279 3105
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012915HARMONIC2
X-RAY DIFFRACTIONt_angle_deg13972HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1001SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes71HARMONIC2
X-RAY DIFFRACTIONt_gen_planes425HARMONIC5
X-RAY DIFFRACTIONt_it2915HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion16.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion378SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3493SEMIHARMONIC4
LS refinement shellResolution: 2.15→2.23 Å / Rfactor Rfree error: 0 / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.253 144 5 %
Rwork0.204 2734 -
all0.207 2878 -
obs--99.41 %
Refinement TLS params.Method: refined / Origin x: -1.8722 Å / Origin y: -26.2188 Å / Origin z: 21.8241 Å
111213212223313233
T-0.1067 Å20.0315 Å2-0.0269 Å2--0.0467 Å20.0262 Å2--0.0419 Å2
L0.5253 °20.1421 °2-0.4138 °2-0.5428 °20.0633 °2--0.78 °2
S-0.0212 Å °-0.0001 Å °-0.0415 Å °0.0313 Å °0.037 Å °-0.0018 Å °-0.0045 Å °-0.0104 Å °-0.0158 Å °
Refinement TLS groupSelection details: { A|* }

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