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- PDB-8our: CRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 16 -

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Basic information

Entry
Database: PDB / ID: 8our
TitleCRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 16
ComponentsMitogen-activated protein kinase kinase kinase 12
KeywordsSIGNALING PROTEIN / DLK / KINASE / INHIBITOR / TRANSFERASE-INHIBITOR / M3K12
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 / cytosol / cytoplasm
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 / 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
Chem-W38 / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsZebisch, M. / McEwan, P.A. / Barker, J.J. / Cross, J.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Alzheimers Drug Discovery Foundation (ADDF)20160903 United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.
Authors: Le, K. / Soth, M.J. / Cross, J.B. / Liu, G. / Ray, W.J. / Ma, J. / Goodwani, S.G. / Acton, P.J. / Buggia-Prevot, V. / Akkermans, O. / Barker, J. / Conner, M.L. / Jiang, Y. / Liu, Z. / ...Authors: Le, K. / Soth, M.J. / Cross, J.B. / Liu, G. / Ray, W.J. / Ma, J. / Goodwani, S.G. / Acton, P.J. / Buggia-Prevot, V. / Akkermans, O. / Barker, J. / Conner, M.L. / Jiang, Y. / Liu, Z. / McEwan, P. / Warner-Schmidt, J. / Xu, A. / Zebisch, M. / Heijnen, C.J. / Abrahams, B. / Jones, P.
History
DepositionApr 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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)34,4552
Polymers34,0181
Non-polymers4371
Water2,198122
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.143, 39.241, 59.745
Angle α, β, γ (deg.)90.00, 104.40, 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K12, ZPK / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q12852, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-W38 / 5-[1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)-2-propan-2-yl-imidazol-4-yl]-3-(trifluoromethyloxy)pyridin-2-amine


Mass: 437.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H26F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 35.51 % / Description: thin plates
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.7
Details: 20% PEG 3350, 0.2 M magnesium acetate, and 0.1 M HEPES/NaOH pH 7.5-7.9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.95→32.48 Å / Num. obs: 18960 / % possible obs: 99.8 % / Redundancy: 3.3 % / CC1/2: 0.978 / Rmerge(I) obs: 0.17 / Rpim(I) all: 0.11 / Rrim(I) all: 0.203 / Net I/σ(I): 4.5 / Num. measured all: 63057
Reflection shellResolution: 1.95→2 Å / % possible obs: 99.7 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.902 / Num. measured all: 4399 / Num. unique obs: 1318 / CC1/2: 0.596 / Rpim(I) all: 0.576 / Rrim(I) all: 1.073 / Net I/σ(I) obs: 1.8

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Processing

Software
NameVersionClassification
Aimless0.2.8data scaling
REFMAC5.8.0049refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→35 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.905 / SU B: 11.315 / SU ML: 0.163 / Cross valid method: THROUGHOUT / ESU R: 0.2 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25461 1001 5.3 %RANDOM
Rwork0.1957 ---
obs0.19882 17948 99.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.904 Å2
Baniso -1Baniso -2Baniso -3
1--1.13 Å2-0 Å20.08 Å2
2---1.53 Å20 Å2
3---2.31 Å2
Refinement stepCycle: 1 / Resolution: 1.95→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 31 122 2268
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192250
X-RAY DIFFRACTIONr_bond_other_d0.0010.022170
X-RAY DIFFRACTIONr_angle_refined_deg1.8851.9733076
X-RAY DIFFRACTIONr_angle_other_deg0.95435011
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1635278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.60523.64696
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.9515387
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0591513
X-RAY DIFFRACTIONr_chiral_restr0.1120.2335
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212507
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02516
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.1581.3161070
X-RAY DIFFRACTIONr_mcbond_other1.1491.3141069
X-RAY DIFFRACTIONr_mcangle_it1.9131.9631338
X-RAY DIFFRACTIONr_mcangle_other1.9131.9651339
X-RAY DIFFRACTIONr_scbond_it1.5131.5251180
X-RAY DIFFRACTIONr_scbond_other1.5121.5251181
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.472.2041726
X-RAY DIFFRACTIONr_long_range_B_refined5.53111.2892706
X-RAY DIFFRACTIONr_long_range_B_other5.5311.2922707
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 76 -
Rwork0.257 1295 -
obs--99.56 %
Refinement TLS params.Method: refined / Origin x: 6.3885 Å / Origin y: 2.2951 Å / Origin z: 22.192 Å
111213212223313233
T0.0144 Å20.004 Å2-0.0132 Å2-0.0901 Å20.0284 Å2--0.0254 Å2
L2.0277 °20.247 °20.4378 °2-1.6405 °20.8622 °2--1.5483 °2
S-0.0095 Å °0.065 Å °0.0596 Å °-0.0175 Å °0.0146 Å °0.0689 Å °0.0406 Å °-0.0181 Å °-0.0051 Å °

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