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- PDB-3iph: Crystal structure of p38 in complex with a biphenylamide inhibitor -

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Basic information

Entry
Database: PDB / ID: 3iph
TitleCrystal structure of p38 in complex with a biphenylamide inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / P38 / SERINE/THREONINE PROTEIN KINASE / MAP KINASE / 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 / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / 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 / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / 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
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. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-G11 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsSomers, D.O.
CitationJournal: J.Med.Chem. / Year: 2009
Title: p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.
Authors: Aston, N.M. / Bamborough, P. / Buckton, J.B. / Edwards, C.D. / Holmes, D.S. / Jones, K.L. / Patel, V.K. / Smee, P.A. / Somers, D.O. / Vitulli, G. / Walker, A.L.
History
DepositionAug 17, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Sep 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_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 22, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)42,3739
Polymers41,3751
Non-polymers9988
Water6,179343
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.753, 85.688, 125.206
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 41375.195 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 / Plasmid: pRSETA / Production host: Escherichia coli (E. coli) / Strain (production host): BRL
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-G11 / 6-[5-(cyclopropylcarbamoyl)-2-methylphenyl]-N-(cyclopropylmethyl)pyridine-3-carboxamide


Mass: 349.426 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N3O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 343 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.97 Å3/Da / Density % sol: 58.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 0.1M ADA, 0.18M (NH4)2SO4, 18-20% PEG5000MME, 3-4% Jeffamine ED600, 2mM b-Mercaptoethanol. , pH 6.5, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Nov 22, 2001 / Details: MIRRORS
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→35 Å / Num. obs: 25525 / % possible obs: 86.1 % / Biso Wilson estimate: 27.8 Å2 / Rmerge(I) obs: 0.102 / Χ2: 0.996 / Net I/σ(I): 7.2
Reflection shellResolution: 2.1→2.18 Å / Rmerge(I) obs: 0.542 / Num. unique all: 2513 / Χ2: 0.974 / % possible all: 86.1

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
REFMAC5phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1WFC

1wfc


Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.919 / WRfactor Rfree: 0.234 / WRfactor Rwork: 0.167 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.823 / SU B: 9.89 / SU ML: 0.138 / SU R Cruickshank DPI: 0.206 / SU Rfree: 0.194 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.206 / ESU R Free: 0.194 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1296 5.1 %RANDOM
Rwork0.181 ---
obs0.184 25431 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 74.55 Å2 / Biso mean: 35.344 Å2 / Biso min: 14.55 Å2
Baniso -1Baniso -2Baniso -3
1--0.48 Å20 Å20 Å2
2---0.09 Å20 Å2
3---0.56 Å2
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2803 0 67 343 3213
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222934
X-RAY DIFFRACTIONr_angle_refined_deg1.611.9833977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg11.3195.115349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.1324.088137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.99415498
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8111518
X-RAY DIFFRACTIONr_chiral_restr0.110.2439
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212194
X-RAY DIFFRACTIONr_mcbond_it1.06321735
X-RAY DIFFRACTIONr_mcangle_it1.87532816
X-RAY DIFFRACTIONr_scbond_it3.0224.51199
X-RAY DIFFRACTIONr_scangle_it4.38561157
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 78 -
Rwork0.322 1748 -
all-1826 -
obs--100 %
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)
11.38471.1452-0.12272.9515-1.58193.2112-0.16890.0958-0.0796-0.41140.07820.02050.1867-0.03220.0907-0.18120.00780.0013-0.12790.0196-0.077831.894830.049229.0462
22.4129-1.61430.15963.1703-0.12681.2071-0.03670.1207-0.06530.10430.05840.04040.04310.0524-0.0217-0.1671-0.0160.0037-0.1445-0.0095-0.246152.262122.796449.2879
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 109
2X-RAY DIFFRACTION1A318 - 352
3X-RAY DIFFRACTION2A110 - 317

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