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- PDB-5ceo: DLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)... -

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Basic information

Entry
Database: PDB / ID: 5ceo
TitleDLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile
ComponentsMitogen-activated protein kinase kinase kinase 12
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / kinase / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


mitogen-activated protein kinase kinase kinase / JUN kinase kinase kinase activity / negative regulation of motor neuron apoptotic process / positive regulation of protein kinase activity / positive regulation of JUN kinase activity / JNK cascade / protein serine/threonine kinase activator activity / post-translational protein modification / growth cone / peptidyl-serine phosphorylation ...mitogen-activated protein kinase kinase kinase / JUN kinase kinase kinase activity / negative regulation of motor neuron apoptotic process / positive regulation of protein kinase activity / positive regulation of JUN kinase activity / JNK cascade / protein serine/threonine kinase activator activity / post-translational protein modification / growth cone / peptidyl-serine phosphorylation / protein autophosphorylation / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / positive regulation of DNA-templated transcription / protein homodimerization activity / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Mitogen-activated protein kinase kinase kinase 12/13 / Mitogen-activated protein kinase kinase kinase 12 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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. ...Mitogen-activated protein kinase kinase kinase 12/13 / Mitogen-activated protein kinase kinase kinase 12 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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. / 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-50D / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.28 Å
AuthorsHARRIS, S.F. / YIN, J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12).
Authors: Patel, S. / Harris, S.F. / Gibbons, P. / Deshmukh, G. / Gustafson, A. / Kellar, T. / Lin, H. / Liu, X. / Liu, Y. / Liu, Y. / Ma, C. / Scearce-Levie, K. / Ghosh, A.S. / Shin, Y.G. / Solanoy, ...Authors: Patel, S. / Harris, S.F. / Gibbons, P. / Deshmukh, G. / Gustafson, A. / Kellar, T. / Lin, H. / Liu, X. / Liu, Y. / Liu, Y. / Ma, C. / Scearce-Levie, K. / Ghosh, A.S. / Shin, Y.G. / Solanoy, H. / Wang, J. / Wang, B. / Yin, J. / Siu, M. / Lewcock, J.W.
History
DepositionJul 7, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4592
Polymers34,0181
Non-polymers4401
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.820, 39.040, 62.790
Angle α, β, γ (deg.)90.000, 107.370, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase 12 / Dual leucine zipper bearing kinase / DLK / Leucine-zipper protein kinase / ZPK / MAPK-upstream ...Dual leucine zipper bearing kinase / DLK / Leucine-zipper protein kinase / ZPK / MAPK-upstream kinase / MUK / Mixed lineage kinase


Mass: 34018.031 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 115-402)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K12, ZPK / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q12852, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-50D / 2-[[6-[3,3-bis(fluoranyl)pyrrolidin-1-yl]-4-[1-(oxetan-3-yl)piperidin-4-yl]pyridin-2-yl]amino]pyridine-4-carbonitrile


Mass: 440.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26F2N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 1.99 Å3/Da / Density % sol: 38.14 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.7
Details: 0.2 M magnesium acetate, 20% PEG 3350, 0.1 M HEPES pH 7.7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 14, 2012
RadiationMonochromator: DOUBLE CRYSTAL Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.28→39.041 Å / Num. all: 11797 / Num. obs: 11797 / % possible obs: 95.4 % / Redundancy: 3.3 % / Biso Wilson estimate: 50.39 Å2 / Rpim(I) all: 0.05 / Rrim(I) all: 0.094 / Rsym value: 0.079 / Net I/av σ(I): 6.845 / Net I/σ(I): 9.3 / Num. measured all: 39517
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.28-2.43.40.6431.1566216760.4030.7620.6431.993.5
2.4-2.553.40.4361.6561116310.270.5140.4362.996.4
2.55-2.733.30.2962.3516315510.1870.3510.2963.996.8
2.73-2.943.30.1773.8471014070.1120.2110.1775.995.5
2.94-3.223.40.1165.9460913490.0720.1370.1168.797.7
3.22-3.63.20.0768.1386411890.0490.0910.07612.696
3.6-4.163.40.05410.9352410300.0330.0640.05418.594
4.16-5.13.30.04313.430099060.0280.0510.04321.696.2
5.1-7.213.20.04115.221526710.0270.0490.04119.492.2
7.21-39.0413.10.04211.312133870.0270.050.04223.392.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.28→35.64 Å / Cor.coef. Fo:Fc: 0.9314 / Cor.coef. Fo:Fc free: 0.8847 / SU R Cruickshank DPI: 0.395 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.394 / SU Rfree Blow DPI: 0.249 / SU Rfree Cruickshank DPI: 0.252
RfactorNum. reflection% reflectionSelection details
Rfree0.2482 606 5.14 %RANDOM
Rwork0.1871 ---
obs0.1902 11788 94.46 %-
Displacement parametersBiso max: 157.6 Å2 / Biso mean: 51.41 Å2 / Biso min: 24.24 Å2
Baniso -1Baniso -2Baniso -3
1--0.2967 Å20 Å214.7176 Å2
2--8.4884 Å20 Å2
3----8.1918 Å2
Refine analyzeLuzzati coordinate error obs: 0.287 Å
Refinement stepCycle: final / Resolution: 2.28→35.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2156 0 32 71 2259
Biso mean--40.96 54.04 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d783SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes337HARMONIC5
X-RAY DIFFRACTIONt_it2257HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2630SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2257HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3068HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion21.05
LS refinement shellResolution: 2.28→2.5 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2965 143 5.15 %
Rwork0.2303 2635 -
all0.2337 2778 -
obs--94.46 %

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