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- PDB-6sou: Fragment N13565a in complex with MAP kinase p38-alpha -

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Basic information

Entry
Database: PDB / ID: 6sou
TitleFragment N13565a in complex with MAP kinase p38-alpha
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / FBDD / Fragment Based Drug Design / P38 / MAPK14 / Kinase / Transferase.
Function / homology
Function and homology information


p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Regulation of MITF-M-dependent genes involved in pigmentation / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Regulation of MITF-M-dependent genes involved in pigmentation / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / Myogenesis / VEGFA-VEGFR2 Pathway / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / D-glucose import / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / Neutrophil degranulation / positive regulation of erythrocyte differentiation / osteoclast differentiation / DNA damage checkpoint signaling / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / cellular response to virus / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / MAPK cascade / cellular response to tumor necrosis factor / kinase activity / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / response to lipopolysaccharide / transcription by RNA polymerase II / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / glutamatergic synapse / regulation of DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase 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
Similarity search - Domain/homology
Chem-LPZ / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsNichols, C.E. / De Nicola, G.F.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
British Heart FoundationSP/14/2/30922 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2020
Title: Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1 ...Title: Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1 beta-IL1R and p38 alpha-TAB1 Complexes.
Authors: Nichols, C. / Ng, J. / Keshu, A. / Kelly, G. / Conte, M.R. / Marber, M.S. / Fraternali, F. / De Nicola, G.F.
History
DepositionAug 29, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)44,5458
Polymers43,8091
Non-polymers7377
Water5,639313
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area730 Å2
ΔGint-53 kcal/mol
Surface area17280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.682, 86.950, 127.035
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 43808.738 Da / Num. of mol.: 1
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
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-LPZ / 2-(4-methylphenoxy)-1-(4-methylpiperazin-4-ium-1-yl)ethanone


Mass: 249.329 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H21N2O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.21 Å3/Da / Density % sol: 61.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 27.5% PEG3350, 0.1M magnesium chloride, 0.1M magnesium sulphate, 0.1M bis-tris propane, 10% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.5→71.75 Å / Num. obs: 81032 / % possible obs: 99.1 % / Redundancy: 6.3 % / Biso Wilson estimate: 18.38 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.2
Reflection shellResolution: 1.5→1.54 Å / Redundancy: 5.3 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 5937 / CC1/2: 0.534 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PHENIX1.16_3549refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SO1

6so1


Resolution: 1.5→71.75 Å / SU ML: 0.2076 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 26.3906
RfactorNum. reflection% reflection
Rfree0.2333 7870 5.08 %
Rwork0.2152 --
obs0.2161 80915 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 25.45 Å2
Refinement stepCycle: LAST / Resolution: 1.5→71.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2699 0 45 313 3057
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00762846
X-RAY DIFFRACTIONf_angle_d0.77873876
X-RAY DIFFRACTIONf_chiral_restr0.0522433
X-RAY DIFFRACTIONf_plane_restr0.0056509
X-RAY DIFFRACTIONf_dihedral_angle_d2.54922338
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.520.3952820.37484967X-RAY DIFFRACTION99.53
1.52-1.530.34162650.36224855X-RAY DIFFRACTION98.71
1.53-1.550.30822350.35394891X-RAY DIFFRACTION98.18
1.55-1.570.38542680.35054921X-RAY DIFFRACTION98.54
1.57-1.590.35092230.3424759X-RAY DIFFRACTION96.76
1.59-1.620.32762650.33084903X-RAY DIFFRACTION98.98
1.62-1.640.32922570.31785002X-RAY DIFFRACTION99.3
1.64-1.660.32812350.31664875X-RAY DIFFRACTION99.24
1.66-1.690.3182530.3095003X-RAY DIFFRACTION99.24
1.69-1.720.31883070.29364787X-RAY DIFFRACTION99.32
1.72-1.750.32283050.28744943X-RAY DIFFRACTION99.47
1.75-1.780.31112350.2954939X-RAY DIFFRACTION99.56
1.78-1.810.29422760.28184894X-RAY DIFFRACTION99.5
1.81-1.850.29762530.27474925X-RAY DIFFRACTION98.93
1.85-1.890.26362700.25284782X-RAY DIFFRACTION96.08
1.89-1.930.26532530.23344824X-RAY DIFFRACTION97.97
1.93-1.980.23112670.22154958X-RAY DIFFRACTION99.43
1.98-2.040.25452260.20954896X-RAY DIFFRACTION99.4
2.04-2.10.1942580.21094958X-RAY DIFFRACTION99.64
2.1-2.160.23852810.20014901X-RAY DIFFRACTION99.33
2.16-2.240.25212530.19864938X-RAY DIFFRACTION99.6
2.24-2.330.23882460.20514932X-RAY DIFFRACTION99.23
2.33-2.440.19553090.19844799X-RAY DIFFRACTION97.78
2.44-2.560.23712660.19344949X-RAY DIFFRACTION99.79
2.56-2.730.2062570.20294943X-RAY DIFFRACTION99.75
2.73-2.940.20152610.20354951X-RAY DIFFRACTION99.75
2.94-3.230.24412830.20064918X-RAY DIFFRACTION99.71
3.23-3.70.19882600.18194799X-RAY DIFFRACTION97.14
3.7-4.660.18422740.1654954X-RAY DIFFRACTION99.81
4.66-71.750.19742470.18614925X-RAY DIFFRACTION99.18

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