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- PDB-5ceq: DLK in complex with inhibitor 2-((1-cyclopentyl-5-(1-(oxetan-3-yl... -

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Basic information

Entry
Database: PDB / ID: 5ceq
TitleDLK in complex with inhibitor 2-((1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-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 / post-translational protein modification / protein serine/threonine kinase activator activity / 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 / post-translational protein modification / protein serine/threonine kinase activator activity / 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 / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein kinase kinase kinase 12/13 / Mitogen-activated protein kinase kinase kinase 12 / : / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site ...Mitogen-activated protein kinase kinase kinase 12/13 / Mitogen-activated protein kinase kinase kinase 12 / : / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-50F / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.911 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)34,4112
Polymers34,0181
Non-polymers3921
Water3,981221
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.404, 39.223, 59.815
Angle α, β, γ (deg.)90.000, 104.800, 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-50F / 2-[[1-cyclopentyl-5-[1-(oxetan-3-yl)piperidin-4-yl]pyrazol-3-yl]amino]pyridine-4-carbonitrile


Mass: 392.497 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H28N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / 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: 1.91 Å3/Da / Density % sol: 35.73 % / Mosaicity: 0 °
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: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 27, 2012
RadiationMonochromator: DOUBLE CRYSTAL Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.911→39.223 Å / Num. all: 19830 / Num. obs: 19830 / % possible obs: 98.3 % / Redundancy: 3.5 % / Biso Wilson estimate: 17.75 Å2 / Rpim(I) all: 0.067 / Rrim(I) all: 0.127 / Rsym value: 0.094 / Net I/av σ(I): 7.276 / Net I/σ(I): 11.3 / Num. measured all: 70341
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
1.91-2.013.60.4551.61025728420.3150.6050.4552.797.8
2.01-2.143.60.3152.3971126910.2160.4150.315497.5
2.14-2.283.60.2213.1924525670.1510.2880.2215.798.2
2.28-2.473.60.1614.1868124120.110.2110.1617.698.5
2.47-2.73.60.1215.5775221790.0850.1620.1219.898.6
2.7-3.023.50.0877.7717020220.0610.1150.08712.998.6
3.02-3.493.50.05712612217610.0410.0760.05718.599
3.49-4.273.30.03817.5498214960.0280.0510.03825.398.5
4.27-6.043.50.0321.1414311840.0220.0410.0328.499.2
6.04-39.2233.40.02622.522786760.0180.0340.02630.397.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.911→35.74 Å / Cor.coef. Fo:Fc: 0.9431 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.167 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.2182 990 5 %RANDOM
Rwork0.1688 ---
obs0.1712 19819 97.67 %-
Displacement parametersBiso max: 132.38 Å2 / Biso mean: 22.04 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-1.6247 Å20 Å23.2546 Å2
2---0.0652 Å20 Å2
3----1.5594 Å2
Refine analyzeLuzzati coordinate error obs: 0.187 Å
Refinement stepCycle: final / Resolution: 1.911→35.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2156 0 29 221 2406
Biso mean--16.16 33.58 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d790SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes340HARMONIC5
X-RAY DIFFRACTIONt_it2270HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion282SEMIHARMONIC5
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_contact2893SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2270HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3087HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3
X-RAY DIFFRACTIONt_other_torsion18.39
LS refinement shellResolution: 1.91→2.01 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2394 151 5.36 %
Rwork0.1926 2668 -
all0.1951 2819 -
obs--97.67 %

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