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- PDB-5vo1: DLK in complex with compound 10 (5-(1-isopropyl-5-(3-(oxetan-3-yl... -

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Basic information

Entry
Database: PDB / ID: 5vo1
TitleDLK in complex with compound 10 (5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine)
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-9FS / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 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)34,4252
Polymers34,0181
Non-polymers4071
Water2,720151
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)57.284, 39.823, 61.702
Angle α, β, γ (deg.)90.000, 105.300, 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-9FS / 5-{5-[(1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-(propan-2-yl)-1H-pyrazol-3-yl}-3-(trifluoromethyl)pyridin-2-amine


Mass: 407.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24F3N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2 Å3/Da / Density % sol: 38.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging 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: ALS / Beamline: 5.0.1 / Wavelength: 0.977408 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977408 Å / Relative weight: 1
ReflectionResolution: 2.446→47.174 Å / Num. obs: 10145 / % possible obs: 99.8 % / Redundancy: 3.6 % / Biso Wilson estimate: 37.26 Å2 / Rpim(I) all: 0.064 / Rrim(I) all: 0.123 / Rsym value: 0.089 / Net I/av σ(I): 8.7 / Net I/σ(I): 12.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
2.45-2.583.70.3762.10.2640.5110.376100
2.58-2.733.70.2922.70.2040.3940.29299.9
2.73-2.923.70.2253.50.1590.3060.22599.8
2.92-3.163.70.1485.30.1040.2010.14899.8
3.16-3.463.60.0968.20.0690.1330.09699.7
3.46-3.873.60.06212.50.0440.0860.06299.8
3.87-4.473.60.042180.030.0570.04299.8
4.47-5.473.50.04118.70.0290.0560.04199.7
5.47-7.733.50.03919.30.0290.0550.03999.9
7.73-47.1743.40.01839.10.0130.0250.01899.6

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Processing

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

5cen


Resolution: 2.45→47.17 Å / Cor.coef. Fo:Fc: 0.9004 / Cor.coef. Fo:Fc free: 0.8271 / SU R Cruickshank DPI: 0.757 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.274 / SU Rfree Blow DPI: 0.288 / SU Rfree Cruickshank DPI: 0.287
RfactorNum. reflection% reflectionSelection details
Rfree0.243 531 5.27 %RANDOM
Rwork0.1664 ---
obs0.1703 10078 99.77 %-
Displacement parametersBiso max: 121.23 Å2 / Biso mean: 33.19 Å2 / Biso min: 10.45 Å2
Baniso -1Baniso -2Baniso -3
1-8.8772 Å20 Å213.038 Å2
2--7.5494 Å20 Å2
3----16.4266 Å2
Refine analyzeLuzzati coordinate error obs: 0.251 Å
Refinement stepCycle: final / Resolution: 2.45→47.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2156 0 29 151 2336
Biso mean--27.6 37.59 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d782SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes337HARMONIC5
X-RAY DIFFRACTIONt_it2263HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion281SEMIHARMONIC5
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_contact2763SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2263HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3081HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion2.62
X-RAY DIFFRACTIONt_other_torsion19.89
LS refinement shellResolution: 2.45→2.74 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2594 142 5.05 %
Rwork0.1916 2668 -
all0.1951 2810 -
obs--99.77 %

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