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- PDB-8pta: JNK1 covalently bound to BD837 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pta
TitleJNK1 covalently bound to BD837 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


JUN phosphorylation / positive regulation of cell killing / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / basal dendrite / positive regulation of establishment of protein localization to mitochondrion / Activation of BIM and translocation to mitochondria / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity ...JUN phosphorylation / positive regulation of cell killing / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / basal dendrite / positive regulation of establishment of protein localization to mitochondrion / Activation of BIM and translocation to mitochondria / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity / NRAGE signals death through JNK / positive regulation of NLRP3 inflammasome complex assembly / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / positive regulation of protein metabolic process / JUN kinase activity / mitogen-activated protein kinase / regulation of macroautophagy / response to UV / response to mechanical stimulus / stress-activated MAPK cascade / energy homeostasis / JNK cascade / protein serine/threonine kinase binding / negative regulation of protein binding / peptidyl-threonine phosphorylation / cellular response to amino acid starvation / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / cellular response to reactive oxygen species / FCERI mediated MAPK activation / regulation of circadian rhythm / histone deacetylase binding / cellular response to mechanical stimulus / 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 / peptidyl-serine phosphorylation / regulation of protein localization / cellular response to lipopolysaccharide / cellular response to oxidative stress / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / protein phosphorylation / positive regulation of apoptotic process / axon / 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: 2.41 Å
AuthorsSok, P. / Poti, A. / Remenyi, A.
Funding support Hungary, 1items
OrganizationGrant numberCountry
National Research Development and Innovation Office (NKFIH)KKP 126963 Hungary
CitationJournal: Nat Commun / Year: 2024
Title: Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.
Authors: Balint, D. / Poti, A.L. / Alexa, A. / Sok, P. / Albert, K. / Torda, L. / Foldesi-Nagy, D. / Csokas, D. / Turczel, G. / Imre, T. / Szarka, E. / Fekete, F. / Bento, I. / Bojtar, M. / Palko, R. ...Authors: Balint, D. / Poti, A.L. / Alexa, A. / Sok, P. / Albert, K. / Torda, L. / Foldesi-Nagy, D. / Csokas, D. / Turczel, G. / Imre, T. / Szarka, E. / Fekete, F. / Bento, I. / Bojtar, M. / Palko, R. / Szabo, P. / Monostory, K. / Papai, I. / Soos, T. / Remenyi, A.
History
DepositionJul 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)127,9687
Polymers126,0983
Non-polymers1,8704
Water48627
1
A: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7173
Polymers42,0331
Non-polymers6852
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6252
Polymers42,0331
Non-polymers5931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6252
Polymers42,0331
Non-polymers5931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)106.256, 106.256, 99.719
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 BD837 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-CIF / methyl (1R,3S)-1-methyl-3-[[3-[[3-methyl-4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]carbamoyl]phenyl]carbamoyl]-4-oxidanylidene-cyclohexane-1-carboxylate


Mass: 592.644 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C33H32N6O5 / 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: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 53.2 % / Description: rod shaped
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 12% PEG 3000, 2-4% MPD, 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: 0.459
ReflectionResolution: 2.41→49.86 Å / Num. obs: 48570 / % possible obs: 99.8 % / Redundancy: 10.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.024 / Rrim(I) all: 0.08 / Χ2: 1.02 / Net I/σ(I): 16 / Num. measured all: 507941
Reflection shellResolution: 2.41→2.49 Å / % possible obs: 98.2 % / Redundancy: 7.3 % / Rmerge(I) obs: 2.334 / Num. measured all: 32070 / Num. unique obs: 4422 / CC1/2: 0.476 / Rpim(I) all: 0.901 / Rrim(I) all: 2.511 / Χ2: 1.1 / Net I/σ(I) obs: 0.9

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→46.89 Å / Cross valid method: THROUGHOUT / σ(F): 149.11 / Phase error: 29.14 / 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-BD837 covalent bond (1.7)
RfactorNum. reflection% reflectionSelection details
Rfree0.2262 1985 4.09 %RANDOM
Rwork0.2097 ---
obs0.2235 48522 99.78 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.41→46.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8277 0 138 27 8442
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.41-2.470.36321330.34673265X-RAY DIFFRACTION93
2.47-2.540.31771520.3283293X-RAY DIFFRACTION96
2.54-2.610.32641450.31163346X-RAY DIFFRACTION96
2.61-2.70.27541480.30853320X-RAY DIFFRACTION96
2.7-2.790.30021380.29433367X-RAY DIFFRACTION96
2.79-2.90.32651420.28883265X-RAY DIFFRACTION96
2.9-3.040.2841460.27953397X-RAY DIFFRACTION96
3.04-3.20.22411400.27263275X-RAY DIFFRACTION96
3.2-3.40.27541380.26133338X-RAY DIFFRACTION96
3.4-3.660.27941460.23873361X-RAY DIFFRACTION96
3.66-4.030.22661380.22543324X-RAY DIFFRACTION96
4.03-4.610.23871400.20513325X-RAY DIFFRACTION96
4.61-5.80.1871320.18193328X-RAY DIFFRACTION96
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)
16.39590.6233-6.69272.9594-0.97957.1437-0.6161-0.051-1.0151-0.0215-0.1583-0.19910.7140.25680.52930.62190.0757-0.00850.53850.0080.588316.0019-69.153310.2011
21.69730.0547-1.09851.1502-0.05051.59480.02430.40760.1142-0.08160.03340.0431-0.1598-0.2775-0.06040.61130.0108-0.02850.6331-0.0070.29422.6541-49.3609-1.9008
33.2333-0.069-0.91963.2035-0.99220.70.0663-0.2369-0.29610.1693-0.5282-0.9174-0.19140.66310.25120.7471-0.1205-0.02630.82090.13280.60667.5761-18.033317.7635
41.16941.31640.11753.3809-1.43671.9352-0.1264-0.02290.09620.23880.0773-0.3581-0.0823-0.03450.05190.56830.0743-0.05430.557-0.06110.360251.0478-18.54213.16
52.31071.5731-1.53491.312-1.02521.07830.1253-0.28440.2853-0.3775-0.46260.15670.4973-0.09140.25140.7841-0.0349-0.0580.6983-0.06280.402847.5964-24.2146-4.3162
62.16050.1626-0.07171.77310.33520.2452-0.05440.3802-0.0639-0.101-0.08510.1123-0.0808-0.43050.06490.6106-0.0238-0.03860.76150.00620.298335.1275-33.11470.2842
71.21481.3463-0.57862.4006-1.26231.1532-0.26720.24150.0379-0.29690.1651-0.3501-0.2452-0.40170.09411.08020.00610.0470.70880.0210.526949.9972-6.57589.4603
89.2910.5854-3.28214.47163.38414.09310.16470.57240.8155-0.2922-0.02940.51890.1162-0.3460.0520.67980.1293-0.09430.62180.05380.6544-8.623115.3136-9.0615
98.3214-2.1991-3.99451.88020.7497.4012-0.28280.45340.01091.12460.32270.5723-0.1251-0.43810.15170.9045-0.04250.12420.62670.06791.09372.100920.10146.6889
100.44050.20590.2512.44-0.45910.2841-0.0037-0.12560.16110.3281-0.00210.35430.01170.71750.09180.9531-0.11530.05151.01390.14920.51721.065622.0633-3.2529
113.60610.26521.51992.53290.11132.50950.16850.48570.05040.2078-0.03030.00670.63650.3465-0.14950.6590.07130.02180.83380.05190.36039.62931.8402-3.0331
126.23270.468-1.38515.30080.40625.77990.4649-0.01481.08140.5297-0.3107-0.14610.49720.4995-0.37520.65240.01230.06510.75940.06360.5158.52847.12522.9691
130.67610.074-0.42190.3371-0.97633.0652-0.1221-0.3453-0.05250.4965-0.1139-0.1149-0.23110.27460.35351.10390.0792-0.05590.9680.09450.549812.6237-6.781517.0833
142.2264-0.10720.75482.07470.56353.58950.0909-0.2009-0.36120.6533-0.0581-0.09190.58070.6097-0.11220.7310.0433-0.03330.83870.04930.589921.322-9.2745-0.6377
154.57571.6593-0.52132.7349-0.67911.05410.236-0.33680.99240.4017-0.1330.5103-0.61130.2985-0.22290.9569-0.1528-0.00380.8827-0.02510.65758.044121.82614.3565
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 8 through 63 )
2X-RAY DIFFRACTION2chain 'A' and (resid 64 through 363 )
3X-RAY DIFFRACTION3chain 'B' and (resid 7 through 63 )
4X-RAY DIFFRACTION4chain 'B' and (resid 64 through 172 )
5X-RAY DIFFRACTION5chain 'B' and (resid 173 through 203 )
6X-RAY DIFFRACTION6chain 'B' and (resid 204 through 321 )
7X-RAY DIFFRACTION7chain 'B' and (resid 322 through 363 )
8X-RAY DIFFRACTION8chain 'C' and (resid 8 through 56 )
9X-RAY DIFFRACTION9chain 'C' and (resid 57 through 78 )
10X-RAY DIFFRACTION10chain 'C' and (resid 79 through 104 )
11X-RAY DIFFRACTION11chain 'C' and (resid 105 through 156 )
12X-RAY DIFFRACTION12chain 'C' and (resid 157 through 182 )
13X-RAY DIFFRACTION13chain 'C' and (resid 186 through 274 )
14X-RAY DIFFRACTION14chain 'C' and (resid 275 through 330 )
15X-RAY DIFFRACTION15chain 'C' and (resid 331 through 361 )

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