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- PDB-9cdx: Crystal structure of DLK with inhibitor bound -

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Basic information

Entry
Database: PDB / ID: 9cdx
TitleCrystal structure of DLK with inhibitor bound
ComponentsMitogen-activated protein kinase kinase kinase 12
KeywordsTRANSFERASE/INHIBITOR / DUAL LEUCINE ZIPPER BEARING KINASE / COMPLEX / INHIBITOR / 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 JUN kinase activity / positive regulation of protein kinase activity / JNK cascade / post-translational protein modification / protein serine/threonine kinase activator activity / peptidyl-serine phosphorylation / growth cone ...mitogen-activated protein kinase kinase kinase / JUN kinase kinase kinase activity / negative regulation of motor neuron apoptotic process / positive regulation of JUN kinase activity / positive regulation of protein kinase activity / JNK cascade / post-translational protein modification / protein serine/threonine kinase activator activity / peptidyl-serine phosphorylation / growth cone / 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 / 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
Similarity search - Domain/homology
: / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsSkene, R.J. / Bell, J.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.
Authors: Lagiakos, H.R. / Zou, Y. / Igawa, H. / Therrien, E. / Lawrenz, M. / Kato, M. / Svensson, M. / Gray, F. / Jensen, K. / Dahlgren, M.K. / Pelletier, R.D. / Dingley, K. / Bell, J.A. / Liu, Z. / ...Authors: Lagiakos, H.R. / Zou, Y. / Igawa, H. / Therrien, E. / Lawrenz, M. / Kato, M. / Svensson, M. / Gray, F. / Jensen, K. / Dahlgren, M.K. / Pelletier, R.D. / Dingley, K. / Bell, J.A. / Liu, Z. / Jiang, Y. / Zhou, H. / Skene, R.J. / Nie, Z.
History
DepositionJun 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)34,3382
Polymers34,0181
Non-polymers3201
Water41423
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.619, 39.960, 62.503
Angle α, β, γ (deg.)90.00, 106.50, 90.00
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 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q12852, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-A1AZP / (5P)-5-[(4R)-6-(propan-2-yl)imidazo[1,5-a]pyridin-1-yl]-3-(trifluoromethyl)pyridin-2-amine


Mass: 320.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15F3N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.03 Å3/Da / Density % sol: 39.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 15.9% PEG 3350, 0.1M Magnesium Acetate, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.38→47.97 Å / Num. obs: 11162 / % possible obs: 99.6 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.187 / Rpim(I) all: 0.161 / Rrim(I) all: 0.248 / Net I/σ(I): 4.2
Reflection shellResolution: 2.38→2.47 Å / Redundancy: 4 % / Rmerge(I) obs: 1.249 / Num. unique obs: 1176 / Rsym value: 1.658 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PRIME-Xrefinement
XDSdata reduction
Aimless0.7.2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.38→47.97 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.284 579 5.2 %
Rwork0.234 --
obs-11155 99.6 %
Solvent computationShrinkage radii: 1.4 Å / Bsol: 64.79 Å2 / ksol: 0.354 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.778 Å20 Å20.488 Å2
2--0.814 Å20 Å2
3---1.964 Å2
Refinement stepCycle: LAST / Resolution: 2.38→47.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2129 0 23 23 2175
Refine LS restraintsType: OPLS 2005X
LS refinement shellResolution: 2.38→2.47 Å / Rfactor Rfree error: 0.019
RfactorNum. reflection% reflection
Rfree0.412 70 6.3 %
Rwork0.391 1115 -
obs--100 %

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