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- PDB-6sov: Fragments KCL_615 and KCL_802 in complex with MAP kinase p38-alpha -

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Entry
Database: PDB / ID: 6sov
TitleFragments KCL_615 and KCL_802 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 / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / Neutrophil degranulation / osteoclast differentiation / positive regulation of erythrocyte 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 / transcription by RNA polymerase II / response to lipopolysaccharide / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / DNA damage response / 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-LOT / (5~{S},7~{R})-3-azanyladamantan-1-ol / Chem-SB4 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.31 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 30, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry
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)42,3969
Polymers41,3791
Non-polymers1,0178
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: Biological entity.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-46 kcal/mol
Surface area16930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.893, 102.685, 103.687
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-405-

CA

21A-640-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 41379.148 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

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Non-polymers , 6 types, 194 molecules

#2: Chemical ChemComp-SB4 / 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE / SB220025


Mass: 338.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19FN6
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-LOT / 6-[2,5-bis(oxidanylidene)pyrrolidin-1-yl]pyridine-3-sulfonamide


Mass: 255.250 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H9N3O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-LOW / (5~{S},7~{R})-3-azanyladamantan-1-ol


Mass: 167.248 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17NO / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.72 Å3/Da / Density % sol: 54.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 15% PEG400, 5% PEG550-MME, 0.1M calcium acetate, 0.1M MES pH6.0

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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: Jan 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.31→63.54 Å / Num. obs: 103341 / % possible obs: 99.89 % / Redundancy: 6.4 % / Biso Wilson estimate: 14.31 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.3
Reflection shellResolution: 1.31→1.33 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 5009 / CC1/2: 0.519 / % possible all: 98.1

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Processing

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

6so1


Resolution: 1.31→63.54 Å / SU ML: 0.2099 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.5321
RfactorNum. reflection% reflection
Rfree0.2365 5043 5 %
Rwork0.2208 --
obs0.2216 100873 97.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 19.61 Å2
Refinement stepCycle: LAST / Resolution: 1.31→63.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2719 0 63 186 2968
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00572945
X-RAY DIFFRACTIONf_angle_d0.82964031
X-RAY DIFFRACTIONf_chiral_restr0.0781455
X-RAY DIFFRACTIONf_plane_restr0.0045524
X-RAY DIFFRACTIONf_dihedral_angle_d3.10521708
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.31-1.320.41531520.41823050X-RAY DIFFRACTION93.03
1.32-1.340.45441560.40853051X-RAY DIFFRACTION94.69
1.34-1.360.40541690.41883018X-RAY DIFFRACTION94.54
1.36-1.370.42631770.40023122X-RAY DIFFRACTION95.43
1.37-1.390.36311320.39273117X-RAY DIFFRACTION94.56
1.39-1.410.37981830.37363061X-RAY DIFFRACTION95.78
1.41-1.430.391840.36363115X-RAY DIFFRACTION96.07
1.43-1.450.36391840.34583123X-RAY DIFFRACTION96.98
1.45-1.480.35721840.32823110X-RAY DIFFRACTION96.6
1.48-1.50.34381490.30843187X-RAY DIFFRACTION97.15
1.5-1.530.35591730.29923172X-RAY DIFFRACTION96.98
1.53-1.550.34751610.29973157X-RAY DIFFRACTION96.93
1.55-1.580.31541870.27983130X-RAY DIFFRACTION97.44
1.58-1.620.31611670.27163196X-RAY DIFFRACTION98.1
1.62-1.650.32651800.25543184X-RAY DIFFRACTION97.73
1.65-1.690.25581990.2593152X-RAY DIFFRACTION97.7
1.69-1.730.23231430.24583228X-RAY DIFFRACTION97.6
1.73-1.780.24471580.23663203X-RAY DIFFRACTION98.07
1.78-1.830.23561710.21433181X-RAY DIFFRACTION98.07
1.83-1.890.23321510.21363260X-RAY DIFFRACTION98.58
1.89-1.960.22111770.20373188X-RAY DIFFRACTION98.42
1.96-2.040.21471740.2013262X-RAY DIFFRACTION98.93
2.04-2.130.18671710.18813247X-RAY DIFFRACTION99.22
2.13-2.240.20951710.18833251X-RAY DIFFRACTION98.9
2.24-2.380.23981890.18593259X-RAY DIFFRACTION99.14
2.38-2.560.19691520.20793283X-RAY DIFFRACTION99.19
2.56-2.820.22571760.20233293X-RAY DIFFRACTION99.6
2.82-3.230.22711630.20293337X-RAY DIFFRACTION99.63
3.23-4.070.16411520.17873376X-RAY DIFFRACTION99.89
4.07-63.540.18321580.18543517X-RAY DIFFRACTION99.92

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