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- PDB-6y80: Fragment KCL_916 in complex with MAP kinase p38-alpha -

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Basic information

Entry
Database: PDB / ID: 6y80
TitleFragment KCL_916 in complex with MAP kinase p38-alpha
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / FBDD / FRAGMENT BASED DRUG DESIGN / P38 / MAPK14 / KINASE
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 / 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 / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / 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 / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / 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 / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / NFAT protein binding / positive regulation of myotube differentiation / regulation of cytokine production involved in inflammatory response / D-glucose import / p38MAPK cascade / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / vascular endothelial growth factor receptor signaling pathway / positive regulation of myoblast differentiation / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / positive regulation of brown fat cell differentiation / striated muscle cell differentiation / response to muscle stretch / Neutrophil degranulation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / positive regulation of D-glucose import / stem cell differentiation / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cellular response to virus / positive regulation of protein import into nucleus / glucose metabolic process / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / spindle pole / osteoblast differentiation / cellular response to tumor necrosis factor / kinase activity / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / protein phosphatase binding / 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 / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / glutamatergic synapse / 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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
1-(2-adamantylmethyl)-3-ethyl-guanidine / Chem-SB4 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.24 Å
AuthorsDe Nicola, G.F. / Nichols, C.E.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
British Heart FoundationSP/14/2/30922, FS/14/29/30896 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_PC_17164 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
DepositionMar 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 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)42,1889
Polymers41,3221
Non-polymers8668
Water4,594255
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1350 Å2
ΔGint-52 kcal/mol
Surface area17180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.940, 102.344, 103.348
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-406-

CA

21A-629-

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: 41322.098 Da / Num. of mol.: 1 / Mutation: C162S
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, 263 molecules

#2: Chemical ChemComp-OFZ / 1-(2-adamantylmethyl)-3-ethyl-guanidine


Mass: 235.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H25N3 / Feature type: SUBJECT OF INVESTIGATION
#3: 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
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#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.: 255 / 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: 2.59 Å3/Da / Density % sol: 52.5 %
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: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.24→63.72 Å / Num. obs: 121002 / % possible obs: 100 % / Redundancy: 14.7 % / Biso Wilson estimate: 14.8 Å2 / CC1/2: 1 / Net I/σ(I): 14.7
Reflection shellResolution: 1.24→1.27 Å / Redundancy: 6.5 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 8854 / CC1/2: 0.575 / % possible all: 99.9

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Processing

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

6sov


Resolution: 1.24→63.72 Å / SU ML: 0.1799 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 28.0243
RfactorNum. reflection% reflection
Rfree0.2254 11994 5.11 %
Rwork0.2102 --
obs0.211 120937 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 23.12 Å2
Refinement stepCycle: LAST / Resolution: 1.24→63.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2763 0 52 255 3070
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00522961
X-RAY DIFFRACTIONf_angle_d0.80824040
X-RAY DIFFRACTIONf_chiral_restr0.0726456
X-RAY DIFFRACTIONf_plane_restr0.0044519
X-RAY DIFFRACTIONf_dihedral_angle_d17.11371107
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.24-1.250.40624140.40657272X-RAY DIFFRACTION98.92
1.25-1.270.37323760.39787397X-RAY DIFFRACTION99.73
1.27-1.280.40374470.38677439X-RAY DIFFRACTION99.65
1.28-1.30.38424250.37047431X-RAY DIFFRACTION99.73
1.3-1.320.4013890.36277393X-RAY DIFFRACTION99.68
1.32-1.340.36524470.35117391X-RAY DIFFRACTION99.63
1.34-1.350.33964750.34597282X-RAY DIFFRACTION99.7
1.35-1.380.35484170.3337382X-RAY DIFFRACTION99.46
1.38-1.40.31393910.31597485X-RAY DIFFRACTION99.66
1.4-1.420.30753620.29787362X-RAY DIFFRACTION99.69
1.42-1.440.31133890.28417466X-RAY DIFFRACTION99.59
1.44-1.470.28893910.26937395X-RAY DIFFRACTION99.67
1.47-1.50.25033600.25137493X-RAY DIFFRACTION99.83
1.5-1.530.26623830.24227445X-RAY DIFFRACTION99.83
1.53-1.560.22224200.23837354X-RAY DIFFRACTION99.91
1.56-1.60.2443550.22987566X-RAY DIFFRACTION99.85
1.6-1.640.24124010.21827343X-RAY DIFFRACTION99.69
1.64-1.680.22083300.21527495X-RAY DIFFRACTION99.47
1.68-1.730.21654510.21147384X-RAY DIFFRACTION99.69
1.73-1.790.23924270.21347353X-RAY DIFFRACTION99.85
1.79-1.850.24664060.2127451X-RAY DIFFRACTION99.97
1.85-1.930.19833520.20347464X-RAY DIFFRACTION99.97
1.93-2.010.20993920.1957471X-RAY DIFFRACTION100
2.01-2.120.21963900.18887410X-RAY DIFFRACTION99.97
2.12-2.250.1954640.18447420X-RAY DIFFRACTION99.97
2.25-2.430.20754450.1897303X-RAY DIFFRACTION99.32
2.43-2.670.22493860.1937480X-RAY DIFFRACTION99.94
2.67-3.060.1913570.19557458X-RAY DIFFRACTION99.96
3.06-3.850.24220.17737402X-RAY DIFFRACTION99.85
3.85-63.720.18053300.17397511X-RAY DIFFRACTION99.75

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