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- PDB-4tyh: Ternary complex of P38 and MK2 with a P38 inhibitor -

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Basic information

Entry
Database: PDB / ID: 4tyh
TitleTernary complex of P38 and MK2 with a P38 inhibitor
Components
  • MAP kinase-activated protein kinase 2
  • Mitogen-activated protein kinase 14
KeywordsTransferase/Transferase inhibitor / P38 / MK2 / P38 inhibitor / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


calcium-dependent protein serine/threonine kinase activity / macropinocytosis / CREB phosphorylation / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / leukotriene metabolic process / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA ...calcium-dependent protein serine/threonine kinase activity / macropinocytosis / CREB phosphorylation / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / leukotriene metabolic process / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / Regulation of TP53 Activity through Phosphorylation / Myogenesis / regulation of tumor necrosis factor production / VEGFA-VEGFR2 Pathway / regulation of tumor necrosis factor-mediated signaling pathway / calcium/calmodulin-dependent protein kinase activity / regulation of interleukin-6 production / mitogen-activated protein kinase binding / regulation of synaptic membrane adhesion / positive regulation of macrophage cytokine production / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / cartilage condensation / cellular response to UV-B / toll-like receptor signaling pathway / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / inner ear development / response to dietary excess / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / Regulation of HSF1-mediated heat shock response / 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 / regulation of cellular response to heat / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / regulation of mRNA stability / positive regulation of interleukin-12 production / Neutrophil degranulation / response to cytokine / 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 / Regulation of TNFR1 signaling / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / bone development / cellular response to virus / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / positive regulation of reactive oxygen species metabolic process / positive regulation of tumor necrosis factor production / osteoblast differentiation / kinase activity / MAPK cascade / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / Oxidative Stress Induced Senescence / angiogenesis / response to lipopolysaccharide / transcription by RNA polymerase II
Similarity search - Function
MAP kinase activated protein kinase, C-terminal / 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 ...MAP kinase activated protein kinase, C-terminal / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-39G / Mitogen-activated protein kinase 14 / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3 Å
AuthorsCumming, J.G. / Debreczeni, J.E. / Edfeldt, F. / Evertsson, F. / Harrison, M. / Holdgate, G. / James, M. / Lamont, S. / Oldham, K. / Sullivan, J.E. / Wells, S.
CitationJournal: To Be Published
Title: Discovery of substrate selective, ATP-competitive P38 alpha MAP kinase inhibitors
Authors: Cumming, J.G.
History
DepositionJul 8, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / refine_hist
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: MAP kinase-activated protein kinase 2
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,6693
Polymers80,2422
Non-polymers4271
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5990 Å2
ΔGint-22 kcal/mol
Surface area31000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.726, 87.726, 229.876
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein MAP kinase-activated protein kinase 2 / MK2


Mass: 40385.805 Da / Num. of mol.: 1 / Fragment: UNP residues 51-400
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAPK2 / Production host: Escherichia coli (E. coli)
References: UniProt: P49137, non-specific serine/threonine protein kinase
#2: Protein Mitogen-activated protein kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 39856.621 Da / Num. of mol.: 1 / Fragment: UNP residues 6-353
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase
#3: Chemical ChemComp-39G / N-[5-(dimethylsulfamoyl)-2-methylphenyl]-1-phenyl-5-propyl-1H-pyrazole-4-carboxamide


Mass: 426.532 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N4O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.86 Å3/Da / Density % sol: 56.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion / Details: 9% PEG 4K, 100mM NaCit, pH 5.6 / PH range: 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 14, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 3→100 Å / Num. obs: 18845 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 7.86 % / Rmerge(I) obs: 0.2 / Net I/σ(I): 5.7
Reflection shellResolution: 3→3.11 Å / Redundancy: 7.94 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 2 / % possible all: 100

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Processing

SoftwareName: REFMAC / Version: 5.5.0090 / Classification: refinement
RefinementResolution: 3→43.85 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.873 / SU B: 53.929 / SU ML: 0.439 / Cross valid method: THROUGHOUT / ESU R Free: 0.528 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31254 963 5.1 %RANDOM
Rwork0.22828 ---
obs0.2324 17806 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 36.081 Å2
Baniso -1Baniso -2Baniso -3
1-2.18 Å20 Å20 Å2
2--2.18 Å20 Å2
3----4.37 Å2
Refinement stepCycle: 1 / Resolution: 3→43.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5406 0 30 1 5437
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0225561
X-RAY DIFFRACTIONr_bond_other_d0.0010.023794
X-RAY DIFFRACTIONr_angle_refined_deg1.2921.9667535
X-RAY DIFFRACTIONr_angle_other_deg0.84839266
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.765671
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.86324.111253
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.93615993
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2041535
X-RAY DIFFRACTIONr_chiral_restr0.0710.2839
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0216076
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021083
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_it0.4561.53372
X-RAY DIFFRACTIONr_mcbond_other0.0491.51346
X-RAY DIFFRACTIONr_mcangle_it0.85825461
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.90332189
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.6234.52073
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 87 -
Rwork0.322 1257 -
obs--99.85 %
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)
11.4378-0.078-0.35720.41360.12840.6060.02460.10520.0357-0.022-0.03570.07770.0477-0.05840.01110.0540.0307-0.00720.08430.00860.020572.668246.4941104.3223
21.6582-0.1306-0.69011.5206-0.42651.7696-0.0362-0.0678-0.3144-0.10990.06030.05760.23730.118-0.02420.03850.0182-0.01280.02430.00810.079194.411834.378399.8943
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A51 - 400
2X-RAY DIFFRACTION2B6 - 353

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