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- PDB-8pt8: JNK1 covalently bound to RU135 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pt8
TitleJNK1 covalently bound to RU135 cyclohexenone based inhibitor
ComponentsMitogen-activated protein kinase 8
KeywordsSIGNALING PROTEIN / MAPK kinase / MAPK / inhibitor / covalent / JNK / Michael acceptor warhead
Function / homology
Function and homology information


positive regulation of cell killing / JUN phosphorylation / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity ...positive regulation of cell killing / JUN phosphorylation / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity / positive regulation of NLRP3 inflammasome complex assembly / NRAGE signals death through JNK / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / mitogen-activated protein kinase / regulation of macroautophagy / response to UV / stress-activated MAPK cascade / response to mechanical stimulus / protein serine/threonine kinase binding / energy homeostasis / JNK cascade / cellular response to cadmium ion / positive regulation of protein metabolic process / NRIF signals cell death from the nucleus / cellular response to amino acid starvation / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / negative regulation of protein binding / FCERI mediated MAPK activation / peptidyl-threonine phosphorylation / regulation of circadian rhythm / histone deacetylase binding / cellular response to reactive oxygen species / cellular response to mechanical stimulus / regulation of protein localization / cellular senescence / Signaling by ALK fusions and activated point mutants / rhythmic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / cellular response to oxidative stress / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / positive regulation of apoptotic process / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / synapse / positive regulation of gene expression / negative regulation of apoptotic process / enzyme binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / : / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Mitogen-activated protein kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.78 Å
AuthorsSok, P. / Poti, A. / Remenyi, A.
Funding support Hungary, 1items
OrganizationGrant numberCountry
National Research Development and Innovation Office (NKFIH)KKP 126963 Hungary
CitationJournal: To Be Published
Title: Tunable c-Jun N-terminal kinase (JNK) inhibitors that target a specific cysteine by a reversible covalent bond
Authors: Sok, P. / Poti, A. / Balint, D. / Remenyi, A. / Soos, T.
History
DepositionJul 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 8
B: Mitogen-activated protein kinase 8
C: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,0107
Polymers126,0983
Non-polymers1,9124
Water905
1
A: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6392
Polymers42,0331
Non-polymers6071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6392
Polymers42,0331
Non-polymers6071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7313
Polymers42,0331
Non-polymers6992
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)107.720, 107.720, 99.085
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein Mitogen-activated protein kinase 8 / MAP kinase 8 / MAPK 8 / JNK-46 / Stress-activated protein kinase 1c / SAPK1c / Stress-activated ...MAP kinase 8 / MAPK 8 / JNK-46 / Stress-activated protein kinase 1c / SAPK1c / Stress-activated protein kinase JNK1 / c-Jun N-terminal kinase 1


Mass: 42032.566 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: The dephosphorylated inactive JNK1-beta-1 kinase with RU135 covalent inhibitor at the ATP binding pocket
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8, SAPK1, SAPK1C / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P45983, mitogen-activated protein kinase
#2: Chemical ChemComp-A3O / methyl (1R,3R)-1-methyl-3-[[3-[[3-methyl-4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]carbamoyl]phenyl]methylcarbamoyl]-4-oxidanylidene-cyclohexane-1-carboxylate


Mass: 606.671 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H34N6O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.68 Å3/Da / Density % sol: 54.1 % / Description: rod shaped
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 8% PEG 3350, 0.1 M HEPES pH 7.5

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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: 0.9763 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
Reflection twinType: merohedral / Operator: -h,-k,l / Fraction: 0.418
ReflectionResolution: 2.78→49.54 Å / Num. obs: 32361 / % possible obs: 99.9 % / Redundancy: 10.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.031 / Rrim(I) all: 0.104 / Χ2: 1 / Net I/σ(I): 18 / Num. measured all: 349063
Reflection shellResolution: 2.78→2.93 Å / % possible obs: 99.9 % / Redundancy: 10.8 % / Rmerge(I) obs: 2.316 / Num. measured all: 51175 / Num. unique obs: 4757 / CC1/2: 0.518 / Rpim(I) all: 0.737 / Rrim(I) all: 2.432 / Χ2: 0.99 / Net I/σ(I) obs: 1.4

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Processing

Software
NameVersionClassification
PHENIX1.20.1refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.78→47.32 Å / Cross valid method: THROUGHOUT / σ(F): 122.29 / Phase error: 26.63 / Stereochemistry target values: TWIN_LSQ_F
Details: Merohedral twinning was identified in the crystal lattice. The structure was refined with Phenix using -H,-K, L twin operator. Finally untwinned structure factors were generated by Phenix ...Details: Merohedral twinning was identified in the crystal lattice. The structure was refined with Phenix using -H,-K, L twin operator. Finally untwinned structure factors were generated by Phenix and uploaded to keep compatibility with the PDB deposition pipeline detwinning process. Ideal bond length restraints were used for the 116CYS-RU135 covalent bond (1.7)
RfactorNum. reflection% reflectionSelection details
Rfree0.2184 1999 6.18 %RANDOM
Rwork0.2059 ---
obs0.2194 32333 99.93 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.78→47.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8213 0 141 5 8359
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.78-2.850.34311400.3162167X-RAY DIFFRACTION94
2.85-2.930.30941460.30472234X-RAY DIFFRACTION94
2.93-3.010.2591420.30322125X-RAY DIFFRACTION94
3.01-3.110.30951350.28172192X-RAY DIFFRACTION94
3.11-3.220.32991360.28172130X-RAY DIFFRACTION94
3.22-3.350.32461450.2682192X-RAY DIFFRACTION94
3.35-3.50.29811380.2422130X-RAY DIFFRACTION94
3.5-3.690.26511420.24952177X-RAY DIFFRACTION94
3.69-3.920.23311470.22742167X-RAY DIFFRACTION94
3.92-4.220.20951420.21562169X-RAY DIFFRACTION94
4.22-4.640.21581480.19842158X-RAY DIFFRACTION94
4.65-5.320.17821490.19232158X-RAY DIFFRACTION93
5.32-6.690.21391400.20352182X-RAY DIFFRACTION94
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)
11.88060.4315-0.97462.7897-0.6471.4047-0.1113-0.4906-0.21050.3705-0.2815-0.45420.0633-0.55260.39931.0892-0.2783-0.07121.30070.07820.585267.3667-18.09178.2072
22.26191.1913-0.44881.8496-1.07510.5703-0.08770.06180.1103-0.10330.0704-0.0466-0.16190.03780.00370.71190.06160.01180.7669-0.0370.372548.2704-23.087-2.504
32.27190.0656-0.10592.68370.59090.184-0.00750.53040.018-0.5603-0.06130.14480.0292-0.27190.05160.71950.0495-0.08060.8431-0.0260.381932.1665-33.8448-9.6311
41.1591.5447-1.27452.9352-1.66221.34220.3974-0.195-0.14760.616-0.233-0.464-1.0165-0.0403-0.17161.0854-0.04640.09140.820.04530.775449.3825-7.1650.6491
51.19110.341-0.84451.2421-0.67820.74-0.189-0.1306-0.2685-0.0715-0.0576-0.25790.40970.13620.23710.82650.1651-0.01740.91490.01540.488514.9296-64.4194-3.0745
62.70230.0161-0.99182.5515-0.30180.3692-0.11950.8412-0.1009-0.41080.125-0.02690.07-0.4928-0.03840.6339-0.0425-0.02690.7567-0.01670.39920.2698-50.8807-14.2183
71.44230.1463-0.77622.66081.64432.9284-0.39390.35880.1856-0.4336-0.11920.4704-0.3716-0.1880.50770.81880.1527-0.12541.07870.10870.6266-13.3268-43.6968-19.6886
84.0681-1.9659-0.01282.1683-1.39881.66470.14410.24680.05230.4109-0.17830.1214-0.46190.13080.03390.7152-0.0390.0280.6169-0.04360.615612.0818-45.7212-9.3146
90.96090.61830.71891.14281.03751.0165-0.24060.08740.2065-0.1182-0.32770.2431-0.34570.30080.56541.06310.1389-0.10411.15930.03790.57050.195615.5033-10.253
102.48170.36450.58632.3825-0.22350.17080.3045-0.23180.12150.2443-0.2282-0.16440.2791-0.273-0.08730.91250.18190.04331.04470.06660.516512.5524-0.3915-1.9154
110.8847-0.2459-0.81691.39340.88021.5667-0.3212-0.4351-0.2510.97490.01790.1940.8690.60330.29071.15610.05570.02670.82310.10220.666612.707-14.98717.4415
121.74810.1901-0.28513.45210.84962.0149-0.24830.3280.0136-0.17280.5778-0.52890.19360.1613-0.34080.9283-0.030.05181.3071-0.22350.665623.6737-4.8044-7.1833
137.608-2.75142.27865.4656-1.8242.1179-0.5619-0.75760.8250.04390.2328-0.37380.0488-0.01090.33071.0129-0.218-0.01920.8875-0.11780.706612.772325.85610.0978
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 7 through 63 )
2X-RAY DIFFRACTION2chain 'A' and (resid 64 through 241 )
3X-RAY DIFFRACTION3chain 'A' and (resid 242 through 321 )
4X-RAY DIFFRACTION4chain 'A' and (resid 322 through 363 )
5X-RAY DIFFRACTION5chain 'B' and (resid 8 through 124 )
6X-RAY DIFFRACTION6chain 'B' and (resid 125 through 241 )
7X-RAY DIFFRACTION7chain 'B' and (resid 242 through 301 )
8X-RAY DIFFRACTION8chain 'B' and (resid 302 through 363 )
9X-RAY DIFFRACTION9chain 'C' and (resid 7 through 124 )
10X-RAY DIFFRACTION10chain 'C' and (resid 125 through 220 )
11X-RAY DIFFRACTION11chain 'C' and (resid 221 through 301 )
12X-RAY DIFFRACTION12chain 'C' and (resid 302 through 335 )
13X-RAY DIFFRACTION13chain 'C' and (resid 336 through 362 )

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