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- PDB-8out: CRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 22 -

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Basic information

Entry
Database: PDB / ID: 8out
TitleCRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 22
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 / 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 / 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-W3C / Mitogen-activated protein kinase kinase kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.935 Å
AuthorsZebisch, M. / Akkermans, O. / 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
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)34,4442
Polymers34,0181
Non-polymers4261
Water1,47782
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)57.043, 38.888, 62.691
Angle α, β, γ (deg.)90.00, 108.73, 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-W3C / (1R)-1-[4-[6-azanyl-5-(trifluoromethyloxy)pyridin-3-yl]-1-(3-fluoranyl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-tris(fluoranyl)ethanol


Mass: 426.289 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13F7N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 1.94 Å3/Da / Density % sol: 36.46 % / Description: thin plates
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.7
Details: 20% PEG 3350, 0.2 M magnesium acetate, 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: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.935→59.37 Å / Num. obs: 13835 / % possible obs: 70.1 % / Redundancy: 3.4 % / CC1/2: 0.995 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.064 / Rrim(I) all: 0.119 / Net I/σ(I): 5.4
Reflection shellResolution: 1.935→2.106 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.838 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 692 / CC1/2: 0.561 / Rpim(I) all: 0.544 / Rrim(I) all: 1.003 / % possible all: 15.8

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Processing

Software
NameVersionClassification
autoPROC1.0.5data scaling
BUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.935→59.37 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.29 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.286 / SU Rfree Blow DPI: 0.198 / SU Rfree Cruickshank DPI: 0.201
RfactorNum. reflection% reflectionSelection details
Rfree0.2288 654 4.73 %RANDOM
Rwork0.1927 ---
obs0.1945 13835 70.1 %-
Displacement parametersBiso mean: 35.44 Å2
Baniso -1Baniso -2Baniso -3
1-3.266 Å20 Å20.7135 Å2
2---2.0847 Å20 Å2
3----1.1813 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 1.935→59.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2138 0 29 82 2249
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0052262HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.763096HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d784SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes390HARMONIC5
X-RAY DIFFRACTIONt_it2249HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.41
X-RAY DIFFRACTIONt_other_torsion16.43
X-RAY DIFFRACTIONt_improper_torsion
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_contact1791SEMIHARMONIC4
LS refinement shellResolution: 1.94→2.07 Å / Total num. of bins used: 33
RfactorNum. reflection% reflection
Rfree0.2501 -4.39 %
Rwork0.229 414 -
all0.2299 433 -
obs--11.88 %
Refinement TLS params.Method: refined / Origin x: 3.2569 Å / Origin y: 2.5382 Å / Origin z: 22.9871 Å
111213212223313233
T-0.0449 Å20.0133 Å20.0245 Å2--0.1231 Å20.0193 Å2---0.0359 Å2
L1.4846 °20.2173 °20.3468 °2-0.8324 °2-0.0104 °2--1.5118 °2
S-0.014 Å °0.0298 Å °0.0464 Å °-0.029 Å °0.055 Å °0.0396 Å °-0.0146 Å °0.061 Å °-0.0409 Å °
Refinement TLS groupSelection details: { A|* }

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