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- PDB-4r3c: Crystal structure of p38 alpha MAP kinase in complex with a novel... -

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Basic information

Entry
Database: PDB / ID: 4r3c
TitleCrystal structure of p38 alpha MAP kinase in complex with a novel isoform selective drug candidate
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Serine/Threonine-protein kinase / Protein Kinase Domain / Transferase / ATP Binding / Phosphorylation / Cytosol / TRANSFERASE-TRANSFERASE 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 / 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 / mitogen-activated protein kinase p38 binding / Platelet sensitization by LDL / positive regulation of muscle cell differentiation / Myogenesis / NFAT protein binding / positive regulation of myotube differentiation / 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 / MAP kinase kinase activity / fatty acid oxidation / 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 / mitogen-activated protein kinase / JUN kinase activity / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte 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 / bone development / cell morphogenesis / platelet activation / cellular response to virus / spindle pole / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / 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 / apoptotic process / positive regulation of gene expression / Neutrophil degranulation / 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-3GF / 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 / PDB entry 4F9W / Resolution: 2.06 Å
AuthorsGrum-Tokars, V.L. / Minasov, G. / Roy, S.M. / Anderson, W.F. / Watterson, D.M.
CitationJournal: ACS Chem Neurosci / Year: 2015
Title: Targeting human central nervous system protein kinases: An isoform selective p38 alpha MAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
Authors: Roy, S.M. / Grum-Tokars, V.L. / Schavocky, J.P. / Saeed, F. / Staniszewski, A. / Teich, A.F. / Arancio, O. / Bachstetter, A.D. / Webster, S.J. / Van Eldik, L.J. / Minasov, G. / Anderson, W.F. ...Authors: Roy, S.M. / Grum-Tokars, V.L. / Schavocky, J.P. / Saeed, F. / Staniszewski, A. / Teich, A.F. / Arancio, O. / Bachstetter, A.D. / Webster, S.J. / Van Eldik, L.J. / Minasov, G. / Anderson, W.F. / Pelletier, J.C. / Watterson, D.M.
History
DepositionAug 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 25, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Nov 27, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / 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_ref_seq_dif.details / _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)45,0705
Polymers44,0321
Non-polymers1,0384
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.850, 74.512, 77.808
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 / 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: 44032.023 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) / Strain (production host): BL21(DE3)pLysS
References: UniProt: Q16539, mitogen-activated protein kinase
#2: 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
#3: Chemical ChemComp-3GF / 6-(4-methylpiperazin-1-yl)-3-(naphthalen-2-yl)-4-(pyridin-4-yl)pyridazine


Mass: 381.473 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N5
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.17 Å3/Da / Density % sol: 43.25 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.075M Ammonium Acetate, 0.1M BisTris (pH 5.5), 16% PEG 10000, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 24, 2013 / Details: Beryllium lenses
RadiationMonochromator: DIAMOND / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.05→30 Å / Num. obs: 24314 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.8 % / Biso Wilson estimate: 35 Å2 / Rmerge(I) obs: 0.062 / Rsym value: 0.062 / Net I/σ(I): 23.17
Reflection shellResolution: 2.05→2.09 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.599 / Mean I/σ(I) obs: 2.37 / Num. unique all: 1188 / Rsym value: 0.599 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-IceMaxdata collection
PHASERphasing
REFMAC5.5.0102refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: PDB entry 4F9W / Resolution: 2.06→29.93 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.95 / SU B: 8.436 / SU ML: 0.116
Isotropic thermal model: Thermal Factors individually Isotropically Refined
Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.196 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21669 1241 5.1 %RANDOM
Rwork0.1755 ---
all0.17761 ---
obs0.17761 23018 99.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.096 Å2
Baniso -1Baniso -2Baniso -3
1--1.46 Å20 Å20 Å2
2---1.49 Å2-0 Å2
3---2.95 Å2
Refinement stepCycle: LAST / Resolution: 2.06→29.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2720 0 77 146 2943
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192992
X-RAY DIFFRACTIONr_bond_other_d0.0010.022833
X-RAY DIFFRACTIONr_angle_refined_deg1.3971.9964080
X-RAY DIFFRACTIONr_angle_other_deg0.70836512
X-RAY DIFFRACTIONr_dihedral_angle_1_deg2.6185357
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.02124.184141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.88815507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7831519
X-RAY DIFFRACTIONr_chiral_restr0.080.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213398
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02709
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3012.9071404
X-RAY DIFFRACTIONr_mcbond_other2.3022.9051403
X-RAY DIFFRACTIONr_mcangle_it3.4374.3441769
X-RAY DIFFRACTIONr_mcangle_other3.4364.3461770
X-RAY DIFFRACTIONr_scbond_it2.9533.3231588
X-RAY DIFFRACTIONr_scbond_other2.9523.3241589
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6744.8442312
X-RAY DIFFRACTIONr_long_range_B_refined7.04624.6613532
X-RAY DIFFRACTIONr_long_range_B_other7.0224.4833498
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.06→2.109 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.266 88 -
Rwork0.23 1541 -
obs-1541 91.67 %
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)
17.67030.7596-0.32085.5228-1.58393.4709-0.0078-0.23310.17840.3770.27170.6783-0.3523-0.1161-0.26390.09190.02330.07290.07480.0790.141350.256974.03321.2532
22.4153-1.3789-0.23594.4999-2.29382.54950.20.04040.07620.1333-0.02930.1294-0.2613-0.092-0.17080.10410.005-0.0020.0267-0.01030.042760.224480.353310.4699
34.29550.44870.12351.4059-0.64181.01130.0892-0.1273-0.06670.0347-0.08350.08110.0595-0.0111-0.00570.12940.00250.00350.05960.01520.017269.948473.054117.6559
46.10662.9830.55957.47951.2590.99070.0611-0.31490.16050.2906-0.19640.330.14310.00140.13530.1093-0.01050.02680.12750.02240.03173.912576.043821.9393
52.53770.5734-0.20113.14160.06330.52290.0566-0.2080.06710.1966-0.0777-0.3815-0.01420.18170.02110.0473-0.0103-0.02180.12090.04230.076290.918482.347717.9495
63.9623-2.64020.78865.7101-2.0791.66340.12650.4536-0.0414-0.4061-0.0530.16730.106-0.1356-0.07340.15180.0167-0.0420.0945-0.00380.017463.904877.07993.7274
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 53
2X-RAY DIFFRACTION2A54 - 92
3X-RAY DIFFRACTION3A93 - 150
4X-RAY DIFFRACTION4A151 - 189
5X-RAY DIFFRACTION5A190 - 309
6X-RAY DIFFRACTION6A310 - 352

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