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- PDB-3tti: Crystal Structure of JNK3 complexed with CC-930, an orally active... -

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Basic information

Entry
Database: PDB / ID: 3tti
TitleCrystal Structure of JNK3 complexed with CC-930, an orally active anti-fibrotic JNK inhibitor
ComponentsMitogen-activated protein kinase 10
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Mitogen-Activated Protein Kinase 10 / jnk3 / Protein Kinase Inhibitors / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm ...JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm / cellular senescence / rhythmic process / Oxidative Stress Induced Senescence / protein phosphorylation / protein serine kinase activity / signal transduction / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-KBI / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsPlantevin-Krenitsky, V. / Nadolny, L. / Delgado, M. / Ayala, L. / Clareen, S. / Hilgraf, R. / Albers, R. / Hegde, S. / D'Sidocky, N. / Sapienza, J. ...Plantevin-Krenitsky, V. / Nadolny, L. / Delgado, M. / Ayala, L. / Clareen, S. / Hilgraf, R. / Albers, R. / Hegde, S. / D'Sidocky, N. / Sapienza, J. / Wright, J. / McCarrick, M. / Bahmanyar, S. / Chamberlain, P. / Delker, S.L. / Muir, J. / Giegel, D. / Xu, L. / Celeridad, M. / Lachowitzer, J. / Bennett, B. / Moghaddam, M. / Khatsenko, O. / Katz, J. / Fan, R. / Bai, A. / Tang, Y. / Shirley, M.A. / Benish, B. / Bodine, T. / Blease, K. / Raymon, H. / Cathers, B.E. / Satoh, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.
Authors: Plantevin Krenitsky, V. / Nadolny, L. / Delgado, M. / Ayala, L. / Clareen, S.S. / Hilgraf, R. / Albers, R. / Hegde, S. / D'Sidocky, N. / Sapienza, J. / Wright, J. / McCarrick, M. / ...Authors: Plantevin Krenitsky, V. / Nadolny, L. / Delgado, M. / Ayala, L. / Clareen, S.S. / Hilgraf, R. / Albers, R. / Hegde, S. / D'Sidocky, N. / Sapienza, J. / Wright, J. / McCarrick, M. / Bahmanyar, S. / Chamberlain, P. / Delker, S.L. / Muir, J. / Giegel, D. / Xu, L. / Celeridad, M. / Lachowitzer, J. / Bennett, B. / Moghaddam, M. / Khatsenko, O. / Katz, J. / Fan, R. / Bai, A. / Tang, Y. / Shirley, M.A. / Benish, B. / Bodine, T. / Blease, K. / Raymon, H. / Cathers, B.E. / Satoh, Y.
History
DepositionSep 14, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2012Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,1903
Polymers52,6491
Non-polymers5412
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.189, 71.202, 106.813
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase 10 / MAP kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase JNK3 / c-Jun N- ...MAP kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase JNK3 / c-Jun N-terminal kinase 3


Mass: 52649.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JNK3, JNK3A, MAPK10, PRKM10 / Plasmid: pET21d / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: P53779, mitogen-activated protein kinase
#2: Chemical ChemComp-KBI / trans-4-({9-[(3S)-tetrahydrofuran-3-yl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl}amino)cyclohexanol


Mass: 448.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23F3N6O2
#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.: 228 / Source method: isolated from a natural source / Formula: H2O

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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: 1.88 Å3/Da / Density % sol: 34.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 100mm MES, 25% PEG 400, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 1 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jun 16, 2011 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 20879 / Num. obs: 19314 / % possible obs: 92.3 % / Observed criterion σ(I): -3 / Redundancy: 3 % / Rmerge(I) obs: 0.08 / Rsym value: 0.08 / Χ2: 1.849 / Net I/σ(I): 10.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.2-2.242.90.5279871.437196.3
2.24-2.282.90.3879522.063193.2
2.28-2.322.90.32710001.38197.1
2.32-2.3730.3139681.397193.4
2.37-2.4230.2629771.411197.3
2.42-2.4830.2739941.407193.7
2.48-2.5430.2319681.541195.6
2.54-2.6130.1889671.57193.1
2.61-2.6930.1989761.636195.7
2.69-2.773.10.1669581.811192.1
2.77-2.8730.1329601.681193.8
2.87-2.993.10.1189671.778193.2
2.99-3.123.10.0999671.9191.9
3.12-3.293.10.0839492.141191.4
3.29-3.493.10.0729642.259191.2
3.49-3.763.10.0679532.674190.5
3.76-4.143.10.0599542.845190.7
4.14-4.743.20.0499482.464187.6
4.74-5.973.20.0449442.05187.2
5.97-503.10.039611.464182.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.5.0109refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→33.06 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.873 / Occupancy max: 1 / Occupancy min: 1 / SU B: 22.148 / SU ML: 0.257 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.314 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3353 984 5.1 %RANDOM
Rwork0.2418 ---
obs0.2464 19284 92.36 %-
all-20879 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 67.08 Å2 / Biso mean: 37.507 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å20 Å20 Å2
2--0.05 Å20 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.2→33.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 38 228 3032
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222871
X-RAY DIFFRACTIONr_angle_refined_deg1.5571.9633887
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9455338
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.00924.231130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.15615515
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.211516
X-RAY DIFFRACTIONr_chiral_restr0.1010.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212138
X-RAY DIFFRACTIONr_mcbond_it0.7391.51708
X-RAY DIFFRACTIONr_mcangle_it1.31322780
X-RAY DIFFRACTIONr_scbond_it1.91531163
X-RAY DIFFRACTIONr_scangle_it2.7714.51107
LS refinement shellResolution: 2.2→2.256 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 73 -
Rwork0.395 1362 -
all-1435 -
obs--94.66 %
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)
10.34950.0968-0.05721.5932-0.49451.87020.0004-0.03670.0938-0.276-0.01280.00780.111-0.03340.01250.06730.01210.00410.2042-0.01420.2031-18.245517.1394-41.4146
20.3804-0.14260.18540.626-0.17380.9037-0.02110.02950.04220.07760.0284-0.0403-0.0151-0.0263-0.00740.00990.0042-0.00870.06750.00530.085-15.758814.7114-12.3146
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A46 - 149
2X-RAY DIFFRACTION1A383 - 400
3X-RAY DIFFRACTION2A150 - 373

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