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- PDB-6tca: Phosphorylated p38 and MAPKAPK2 complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6tca
TitlePhosphorylated p38 and MAPKAPK2 complex with inhibitor
Components
  • MAP kinase-activated protein kinase 2
  • Mitogen-activated protein kinase 14MAPK14
KeywordsSIGNALING PROTEIN / MAPK / MAPKAPK / phosphorylated / p38 / MK2
Function / homology
Function and homology information


macropinocytosis / CREB phosphorylation / calcium-dependent protein serine/threonine kinase activity / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / leukotriene metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of cyclase activity ...macropinocytosis / CREB phosphorylation / calcium-dependent protein serine/threonine kinase activity / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / leukotriene metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of cyclase activity / calmodulin-dependent protein kinase activity / positive regulation of macrophage cytokine production / mitogen-activated protein kinase binding / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of interleukin-6 production / 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 / toll-like receptor signaling pathway / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / stress-activated protein kinase signaling cascade / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / response to dietary excess / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / inner ear development / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / regulation of cellular response to heat / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cardiac muscle cell proliferation / p38MAPK events / regulation of mRNA stability / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / response to cytokine / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / Regulation of TNFR1 signaling / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / NOD1/2 Signaling Pathway / bone development / cell morphogenesis / platelet activation / osteoblast differentiation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / MAPK cascade / cellular senescence / positive regulation of tumor necrosis factor production / cellular response to tumor necrosis factor / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / Oxidative Stress Induced Senescence
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. / 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 ...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. / 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
Similarity search - Domain/homology
Chem-39G / MAP kinase-activated protein kinase 2 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.7 Å
AuthorsSok, P. / Remenyi, A.
Funding support Hungary, 1items
OrganizationGrant numberCountry
European UnioniNEXT: PID 1742, PID 4788 Hungary
CitationJournal: Structure / Year: 2020
Title: MAP Kinase-Mediated Activation of RSK1 and MK2 Substrate Kinases.
Authors: Sok, P. / Gogl, G. / Kumar, G.S. / Alexa, A. / Singh, N. / Kirsch, K. / Sebo, A. / Drahos, L. / Gaspari, Z. / Peti, W. / Remenyi, A.
History
DepositionNov 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
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: MAP kinase-activated protein kinase 2
B: Mitogen-activated protein kinase 14
C: MAP kinase-activated protein kinase 2
D: Mitogen-activated protein kinase 14
E: MAP kinase-activated protein kinase 2
F: Mitogen-activated protein kinase 14
G: MAP kinase-activated protein kinase 2
H: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)340,48612
Polymers338,7808
Non-polymers1,7064
Water0
1
A: MAP kinase-activated protein kinase 2
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,1213
Polymers84,6952
Non-polymers4271
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5360 Å2
ΔGint-33 kcal/mol
Surface area32330 Å2
MethodPISA
2
C: MAP kinase-activated protein kinase 2
D: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,1213
Polymers84,6952
Non-polymers4271
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4440 Å2
ΔGint-18 kcal/mol
Surface area32560 Å2
MethodPISA
3
E: MAP kinase-activated protein kinase 2
F: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,1213
Polymers84,6952
Non-polymers4271
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4860 Å2
ΔGint-24 kcal/mol
Surface area32280 Å2
MethodPISA
4
G: MAP kinase-activated protein kinase 2
H: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,1213
Polymers84,6952
Non-polymers4271
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4850 Å2
ΔGint-26 kcal/mol
Surface area32990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)279.346, 69.286, 221.107
Angle α, β, γ (deg.)90.000, 123.850, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 42889.512 Da / Num. of mol.: 4
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 / MAPK14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / ...MAPK 14 / Cytokine suppressive anti-inflammatory drug-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: 41805.441 Da / Num. of mol.: 4
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)
References: UniProt: Q16539, 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.: 4 / Source method: obtained synthetically / Formula: C22H26N4O3S / Feature type: SUBJECT OF INVESTIGATION
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: 2.62 Å3/Da / Density % sol: 53.1 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 100mM HEPES pH 7.3, 3.5% PEG 8000, 1% MPD, 1% DMSO. 1.0 M(NH4)2SO4 in the reservoir
PH range: 7.1-7.5 / Temp details: room temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.97626 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 3.7→69.56 Å / Num. obs: 37890 / % possible obs: 99.4 % / Redundancy: 3.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.135 / Rpim(I) all: 0.08 / Rrim(I) all: 0.158 / Net I/σ(I): 6.4 / Num. measured all: 144336 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.7-3.863.90.8431814446060.8410.4870.9771.599.6
12.82-69.563.30.03832289880.9960.0240.04521.898.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
PHENIX1.15.2_3472refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YO8, 2OZA

2yo8
PDB Unreleased entry

2oza


Resolution: 3.7→69.556 Å / SU ML: 0.54 / Data cutoff high absF: 3.7 / Data cutoff low absF: 69.556 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 35.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2972 1995 5.28 %random
Rwork0.2514 ---
obs0.2538 37767 98.87 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 320.1 Å2 / Biso mean: 149.5855 Å2 / Biso min: 81.65 Å2
Refinement stepCycle: final / Resolution: 3.7→69.556 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21668 0 120 0 21788
Biso mean--123.64 --
Num. residues----2717
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.7-3.79250.3841410.356253399
3.7925-3.89510.41211410.3439253299
3.8951-4.00970.32751410.3191252599
4.0097-4.13910.31981420.3065252799
4.1391-4.2870.32271410.2962253999
4.287-4.45860.28361420.2663252699
4.4586-4.66150.30841430.263255298
4.6615-4.90720.26581400.2547250998
4.9072-5.21450.26871420.2497253999
5.2145-5.6170.34031410.2751256299
5.617-6.18190.30961440.2752256899
6.1819-7.07570.33051440.2564258199
7.0757-8.91170.29411460.2147262099
8.9117-69.5560.23971470.1844265998

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