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- PDB-8efj: A structural study of selectivity mechanisms for JNK3 and p38 alp... -

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Basic information

Entry
Database: PDB / ID: 8efj
TitleA structural study of selectivity mechanisms for JNK3 and p38 alpha with indazole scaffold probing compounds
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / C-Jun terminal kinase 3 / JNK3 / p38 alpha / Kinase / selectivity
Function / homology
Function and homology information


DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence ...DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / 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 / cellular response to UV-B / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / glucose import / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase activity / regulation of ossification / 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 / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / Neutrophil degranulation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / placenta development / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / 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 / protein phosphatase binding / angiogenesis / cellular response to lipopolysaccharide / 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 / glutamatergic synapse / apoptotic process / DNA damage response / regulation of DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-WHQ / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 Å
AuthorsPark, H. / Feng, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA) United States
CitationJournal: To Be Published
Title: A structural study of selectivity mechanisms for JNK3 and p38 alpha with indazole scaffold probing compounds
Authors: Park, H. / Feng, Y.
History
DepositionSep 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release

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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)43,2684
Polymers42,2381
Non-polymers1,0303
Water3,603200
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.180, 70.440, 77.000
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 / MAPK14 / MAP kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 42238.117 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: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside / Octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical ChemComp-WHQ / (4P)-4-[5-(2-chloro-6-fluoroanilino)-6-(methoxymethyl)-1H-indazol-1-yl]-N-methylthiophene-2-carboxamide


Mass: 444.910 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18ClFN4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 200 / 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: 2.12 Å3/Da / Density % sol: 42.11 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: PEG 4000, Na cacodylate, n-octyl-b-D-glucoside (b-OG)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.31→77 Å / Num. obs: 16246 / % possible obs: 99.8 % / Redundancy: 6.2 % / Biso Wilson estimate: 21.46 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.039 / Net I/σ(I): 30.8
Reflection shellResolution: 2.31→2.4 Å / Rmerge(I) obs: 0.072 / Num. unique obs: 1568 / CC1/2: 0.996

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Processing

Software
NameVersionClassification
PHENIX1.20rc3_4406refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LOO

4loo


Resolution: 2.31→40.88 Å / SU ML: 0.1626 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.4666
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2226 1624 10.03 %
Rwork0.1892 14572 -
obs0.1926 16196 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.03 Å2
Refinement stepCycle: LAST / Resolution: 2.31→40.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2797 0 70 200 3067
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00972935
X-RAY DIFFRACTIONf_angle_d1.15053984
X-RAY DIFFRACTIONf_chiral_restr0.3527446
X-RAY DIFFRACTIONf_plane_restr0.0068504
X-RAY DIFFRACTIONf_dihedral_angle_d9.154397
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.31-2.380.25871340.19811188X-RAY DIFFRACTION99.92
2.38-2.460.24931250.19521204X-RAY DIFFRACTION99.92
2.46-2.550.23531470.20281195X-RAY DIFFRACTION100
2.55-2.650.23551070.20381196X-RAY DIFFRACTION99.47
2.65-2.770.25111530.19151189X-RAY DIFFRACTION99.48
2.77-2.920.25381200.20391198X-RAY DIFFRACTION99.32
2.92-3.10.23111420.21041210X-RAY DIFFRACTION99.85
3.1-3.340.23961320.19511219X-RAY DIFFRACTION99.63
3.34-3.670.20211370.18611207X-RAY DIFFRACTION99.85
3.67-4.20.20481350.15981222X-RAY DIFFRACTION99.2
4.2-5.290.1821430.16471236X-RAY DIFFRACTION100
5.3-40.880.231490.20721308X-RAY DIFFRACTION98.98
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)
11.32339880.5693842722362.276704013071.787734167160.2181090942914.950496886240.03657262922480.03048604026760.0962281300707-0.407263033825-0.03797453388920.292585420611-0.107773090189-0.01989556697590.1149611767060.2080713070140.0652366139095-0.01681859153840.168492276804-0.01218385369920.198235630569-27.906546306514.3923120068-24.2412699556
24.13238882078-0.501271331022-0.7912901683055.247809490090.3089976075123.83745719750.21011963282-0.462169547055-0.2594252654190.302217354061-0.2763578351650.1907094112550.349043009446-0.1730604383070.1090363623410.218484234321-0.0873250181583-0.05694281251270.211498642520.01676796625930.190565294305-31.7798149808-3.01745722809-23.5229199543
31.621011758230.390625623152-0.1853464345661.404580170360.6245376297441.758135751890.09530112238340.07391330803620.08906304077170.115231865566-0.02644666015710.1309663297720.202827178031-0.2992908239910.09056727890410.159576245566-0.0409828175814-0.04166927205650.1127295344290.0009848539651040.0698491219515-22.48744359395.03359506627-20.7886009854
42.13931388241-0.2721252418840.7378319710512.29717638169-0.3480207541251.364431167910.00986716961897-0.0954232969523-0.07408498943920.108282264262-0.02352514870080.1338335415070.122566165018-0.08063602861210.01797410670460.0972088131856-0.02288835173580.01335219881810.0926892213771-0.02448783963380.0829342734322-4.830983465594.66949434855-20.0110490333
51.05183521894-0.303940576173-0.1233114809440.7956719369580.002530499852611.055571529970.05616321895410.02076180053840.0417070509017-0.0163650280554-0.0853483165036-0.1393600896840.03789599160160.1452720850540.04038585832390.0923202988288-0.04401578585570.01430569591110.0935208918397-0.01668439189590.1078859533294.679783025435.54235697412-14.9676267737
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 334 through 360 )334 - 360322 - 348
22chain 'A' and (resid 5 through 43 )5 - 431 - 39
33chain 'A' and (resid 44 through 123 )44 - 12340 - 119
44chain 'A' and (resid 124 through 218 )124 - 218120 - 206
55chain 'A' and (resid 219 through 333 )219 - 333207 - 321

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