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- PDB-5vo2: DLK in complex with inhibitor 5-(1-isopropyl-5-(1-(oxetan-3-yl)pi... -

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Basic information

Entry
Database: PDB / ID: 5vo2
TitleDLK in complex with inhibitor 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine (compound 7)
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-9FV / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.96 Å
AuthorsHARRIS, S.F. / YIN, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.
Authors: Patel, S. / Meilandt, W.J. / Erickson, R.I. / Chen, J. / Deshmukh, G. / Estrada, A.A. / Fuji, R.N. / Gibbons, P. / Gustafson, A. / Harris, S.F. / Imperio, J. / Liu, W. / Liu, X. / Liu, Y. / ...Authors: Patel, S. / Meilandt, W.J. / Erickson, R.I. / Chen, J. / Deshmukh, G. / Estrada, A.A. / Fuji, R.N. / Gibbons, P. / Gustafson, A. / Harris, S.F. / Imperio, J. / Liu, W. / Liu, X. / Liu, Y. / Lyssikatos, J.P. / Ma, C. / Yin, J. / Lewcock, J.W. / Siu, M.
History
DepositionMay 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,4272
Polymers34,0181
Non-polymers4091
Water63135
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.290, 39.463, 60.113
Angle α, β, γ (deg.)90.000, 104.810, 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: UNP residues 115-402
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K12, ZPK / Production host: unidentified baculovirus
References: UniProt: Q12852, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-9FV / 5-{5-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-3-yl}-3-(trifluoromethyl)pyridin-2-amine


Mass: 409.449 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26F3N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 1.93 Å3/Da / Density % sol: 36.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.7 / Details: 20% PEG 3350, 0.2 M Mg Acetate, 0.1 M Hepes pH 7.7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.958→39.463 Å / Num. all: 5586 / Num. obs: 5586 / % possible obs: 99.5 % / Redundancy: 3.6 % / Biso Wilson estimate: 52.17 Å2 / Rpim(I) all: 0.071 / Rrim(I) all: 0.135 / Rsym value: 0.099 / Net I/av σ(I): 7.5 / Net I/σ(I): 11.5 / Num. measured all: 19858
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
2.96-3.123.60.3122.50.2120.4090.312100
3.12-3.313.60.2313.40.1580.3040.23199.5
3.31-3.543.60.1624.80.1120.2170.16299.6
3.54-3.823.60.1176.60.0810.1540.11799.6
3.82-4.183.50.0898.50.0630.1190.08999.2
4.18-4.683.50.06411.70.0460.0870.06499.3
4.68-5.43.50.07110.70.0510.0970.07199.6
5.4-6.613.50.06112.80.0460.0870.06199.3
6.61-9.353.50.03421.40.0250.0470.03499.7
9.35-39.4633.30.01937.20.0150.0270.01998.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.22data extraction
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5CEN

5cen


Resolution: 2.96→35.79 Å / Cor.coef. Fo:Fc: 0.9094 / Cor.coef. Fo:Fc free: 0.7992 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.484
RfactorNum. reflection% reflectionSelection details
Rfree0.2637 315 5.66 %RANDOM
Rwork0.1695 ---
obs0.1743 5569 99.41 %-
Displacement parametersBiso max: 113.07 Å2 / Biso mean: 34.14 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-10.0096 Å20 Å28.3683 Å2
2--1.1953 Å20 Å2
3----11.2049 Å2
Refine analyzeLuzzati coordinate error obs: 0.297 Å
Refinement stepCycle: final / Resolution: 2.96→35.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2156 0 29 35 2220
Biso mean--31.12 19.51 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d777SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes335HARMONIC5
X-RAY DIFFRACTIONt_it2253HARMONIC20
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_contact2648SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2253HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3063HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.3
X-RAY DIFFRACTIONt_other_torsion20.71
LS refinement shellResolution: 2.96→3.31 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2872 85 5.39 %
Rwork0.1813 1492 -
all0.1873 1577 -
obs--99.41 %

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