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- PDB-8uoi: Crystal structure of human NUAK1-MARK3 kinase domain chimera boun... -

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Basic information

Entry
Database: PDB / ID: 8uoi
TitleCrystal structure of human NUAK1-MARK3 kinase domain chimera bound with small molecule inhibitor #65
ComponentsMAP/microtubule affinity-regulating kinase 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Serine/threonine-protein kinase / NUAK1 / MARK3 / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


peptidyl-serine autophosphorylation / negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / tau protein binding / microtubule cytoskeleton organization ...peptidyl-serine autophosphorylation / negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / tau protein binding / microtubule cytoskeleton organization / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / positive regulation of protein binding / Signaling by BRAF and RAF1 fusions / peptidyl-serine phosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / extracellular exosome / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Serine/threonine-protein kinase, active site ...: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / MAP/microtubule affinity-regulating kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDelker, S.L. / Abendroth, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of UCB9386: A Potent, Selective, and Brain-Penetrant Nuak1 Inhibitor Suitable for In Vivo Pharmacological Studies.
Authors: Poullennec, K.G. / Jnoff, E. / Abendroth, J. / Bhuma, N. / Calmiano, M. / Calmus, L. / Cardenas, A. / Courade, J.P. / Delatour, C. / Hall, A. / de Haro, T. / Delker, S.L. / Demaude, T. / ...Authors: Poullennec, K.G. / Jnoff, E. / Abendroth, J. / Bhuma, N. / Calmiano, M. / Calmus, L. / Cardenas, A. / Courade, J.P. / Delatour, C. / Hall, A. / de Haro, T. / Delker, S.L. / Demaude, T. / Gaikwad, N. / Ghavate, D. / Gholap, A.R. / Kierkowicz, M. / Le Mestre, R. / Van Hijfte, N. / Verheijden, S. / Vernerova, K. / De Wever, V. / Waghmode, N.
History
DepositionOct 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MAP/microtubule affinity-regulating kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6667
Polymers37,9031
Non-polymers7636
Water4,071226
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.010, 87.280, 106.550
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein MAP/microtubule affinity-regulating kinase 3 / C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase ...C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase STK10 / Ser/Thr protein kinase PAR-1 / Par-1a / Serine/threonine-protein kinase p78


Mass: 37902.840 Da / Num. of mol.: 1 / Mutation: I62L, V116I, G137K, F141Y, A146E, L72/71R, V205K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MARK3, CTAK1, EMK2 / Production host: Escherichia coli (E. coli)
References: UniProt: P27448, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-X3Q / (7M)-7-[(4S)-imidazo[1,2-b]pyridazin-3-yl]-1-[(1R)-1-phenylethyl]-3-(piperazin-1-yl)pyrido[3,4-b]pyrazin-2(1H)-one


Mass: 452.511 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C25H24N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 226 / 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: 2.58 Å3/Da / Density % sol: 52.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.86
Details: CID102002 (MARK3-NUAK chimera V205K), PID7361-1, 8.0 mg/ml. Tray 314126g7; JCSG_B4 screen: 9.0% (w/V) PEG 8000, 8% (V/V) ethylene glycol, 100mM HEPES free acid / sodium hydroxide pH 7.86; ...Details: CID102002 (MARK3-NUAK chimera V205K), PID7361-1, 8.0 mg/ml. Tray 314126g7; JCSG_B4 screen: 9.0% (w/V) PEG 8000, 8% (V/V) ethylene glycol, 100mM HEPES free acid / sodium hydroxide pH 7.86; 2,5mM BSI109151 / UCB1705233; crystal back soaked over night with 2.5mM UCB1816405; cryo: 25% EG in soak; puck itc9-6
PH range: 7-8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9749 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9749 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 36537 / % possible obs: 99.7 % / Redundancy: 6.44 % / CC1/2: 1 / Rmerge(I) obs: 0.036 / Rrim(I) all: 0.039 / Net I/σ(I): 25.34
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.8-1.850.57925680.850.6431
1.85-1.90.44626130.9210.4881
1.9-1.950.35225570.9550.3811
1.95-2.010.25824680.9770.2791
2.01-2.080.20223920.9860.221
2.08-2.150.14923080.9920.1621
2.15-2.230.11722440.9950.1271
2.23-2.320.09721400.9960.1051
2.32-2.430.0821000.9970.0861
2.43-2.550.06719720.9980.0731
2.55-2.680.0618830.9980.0651
2.68-2.850.04717930.9990.0511
2.85-3.040.03816880.9990.0411
3.04-3.290.03215760.9990.0351
3.29-3.60.02614560.9990.0281
3.6-4.020.022134510.0241
4.02-4.650.021116010.0231
4.65-5.690.02101510.0221
5.69-8.050.01879510.021
8.05-500.01646410.0181

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→43.64 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1976 1963 5.37 %
Rwork0.1646 --
obs0.1662 36525 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→43.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2559 0 54 226 2839
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082699
X-RAY DIFFRACTIONf_angle_d0.9123634
X-RAY DIFFRACTIONf_dihedral_angle_d18.2861054
X-RAY DIFFRACTIONf_chiral_restr0.061396
X-RAY DIFFRACTIONf_plane_restr0.006457
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.29331410.25472337X-RAY DIFFRACTION97
1.85-1.890.25721220.21212467X-RAY DIFFRACTION100
1.89-1.950.2131500.18892426X-RAY DIFFRACTION100
1.95-2.010.22361370.17632463X-RAY DIFFRACTION100
2.01-2.090.22411480.1812440X-RAY DIFFRACTION100
2.09-2.170.24451560.17462426X-RAY DIFFRACTION100
2.17-2.270.21151660.17122427X-RAY DIFFRACTION100
2.27-2.390.20661460.16512453X-RAY DIFFRACTION100
2.39-2.540.21281450.16432467X-RAY DIFFRACTION100
2.54-2.730.19051470.17172465X-RAY DIFFRACTION100
2.73-3.010.22771300.16832506X-RAY DIFFRACTION100
3.01-3.440.1881310.16852488X-RAY DIFFRACTION100
3.44-4.340.16441290.14692543X-RAY DIFFRACTION100
4.34-43.640.17791150.15542654X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
19.20741.9077-1.27564.5203-1.47671.9590.4909-0.7797-0.64520.7071-0.2687-0.06290.8786-0.4596-0.21030.4677-0.0358-0.01810.47180.11560.277-29.3743-27.51832.8248
22.8138-0.12571.2930.9209-0.35882.9455-0.0139-0.211-0.14880.1504-0.0058-0.10070.2951-0.04350.03510.2590.00070.01440.1890.02760.227-29.0184-22.0434-12.1128
36.4972-2.97112.10485.5311-1.64623.07450.34380.4596-1.0126-0.2033-0.2331-0.45550.84740.866-0.07310.46260.1133-0.03080.4219-0.04260.4801-32.7167-32.8945-29.5753
44.2723-0.97290.45982.62440.2263.66690.04620.1963-0.2848-0.0399-0.10040.24630.4146-0.22890.05770.2248-0.0515-0.00020.2173-0.00270.2342-44.1343-22.5698-30.5759
53.04030.75370.49587.10093.10433.5207-0.14390.34540.4142-0.22940.1006-0.1771-0.14340.25160.00270.1797-0.00960.00180.25580.09520.232-33.6756-11.1555-32.7566
61.8533-1.24173.92150.8057-2.65098.2859-0.33780.3770.34220.4906-0.1936-0.108-0.94140.87010.53070.5145-0.1033-0.11360.42360.07570.3923-14.4939-10.9977-4.1046
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 51 through 67 )
2X-RAY DIFFRACTION2chain 'A' and (resid 68 through 204 )
3X-RAY DIFFRACTION3chain 'A' and (resid 210 through 231 )
4X-RAY DIFFRACTION4chain 'A' and (resid 232 through 287 )
5X-RAY DIFFRACTION5chain 'A' and (resid 288 through 313 )
6X-RAY DIFFRACTION6chain 'A' and (resid 314 through 368 )

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