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- PDB-8uol: Crystal structure of human NUAK1-MARK3 (6 mutations) kinase domai... -

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Basic information

Entry
Database: PDB / ID: 8uol
TitleCrystal structure of human NUAK1-MARK3 (6 mutations) kinase domain chimera bound with small molecule inhibitor #31
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: 1.9 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
B: MAP/microtubule affinity-regulating kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,97710
Polymers75,7462
Non-polymers1,2318
Water7,602422
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.150, 94.880, 68.760
Angle α, β, γ (deg.)90.00, 92.55, 90.00
Int Tables number4
Space group name H-MP1211

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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: 37872.793 Da / Num. of mol.: 2 / Mutation: I62L, V116I, G137K, F141Y, A146E, L72/71R
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-X4H / Narazaciclib / 8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile


Mass: 429.517 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 422 / 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: 2.2 Å3/Da / Density % sol: 44.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: JCSG E12 condition: 0.1 M Imidazole pH 8.0, 10 (%v/v) PEG 8000, 2.5mM compound 31)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 61390 / % possible obs: 98.7 % / Redundancy: 4.13 % / CC1/2: 0.999 / Rmerge(I) obs: 0.049 / Net I/σ(I): 17.52
Reflection shellResolution: 1.9→1.95 Å / Rmerge(I) obs: 0.459 / Num. unique obs: 4221 / CC1/2: 0.863

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.19RC4_4035refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UCB INTERNAL STRUCTURE

Resolution: 1.9→47.44 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.211 2051 4 %
Rwork0.171 --
obs0.173 51315 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.96 Å2
Refinement stepCycle: LAST / Resolution: 1.9→47.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms0 5025 88 422 5535
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d05216
X-RAY DIFFRACTIONf_angle_d0.837004
X-RAY DIFFRACTIONf_dihedral_angle_d13.442030
X-RAY DIFFRACTIONf_chiral_restr0.05761
X-RAY DIFFRACTIONf_plane_restr0880
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.940.26861380.23053246X-RAY DIFFRACTION99
1.94-1.990.30131400.21773264X-RAY DIFFRACTION99
1.99-2.050.27771400.20943294X-RAY DIFFRACTION99
2.05-2.110.23731310.19073212X-RAY DIFFRACTION99
2.11-2.180.23051230.17883269X-RAY DIFFRACTION99
2.18-2.250.19381440.17683292X-RAY DIFFRACTION99
2.25-2.340.22151290.17713310X-RAY DIFFRACTION99
2.34-2.450.2211380.18263269X-RAY DIFFRACTION99
2.45-2.580.24131450.18993262X-RAY DIFFRACTION100
2.58-2.740.25511450.19353291X-RAY DIFFRACTION100
2.74-2.950.20561200.1843288X-RAY DIFFRACTION100
2.95-3.250.22741640.17863285X-RAY DIFFRACTION99
3.25-3.720.16531430.16163287X-RAY DIFFRACTION100
3.72-4.680.19221120.13823348X-RAY DIFFRACTION99
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)
12.38850.1746-0.38782.0562-0.28253.8271-0.02020.22740.1071-0.21290.0254-0.0525-0.21450.33450.00320.1884-0.0149-0.00640.1382-0.02120.151831.838-7.810934.2357
21.85791.62640.29782.60650.90831.2474-0.02560.0351-0.0083-0.2056-0.01810.0896-0.0761-0.01520.03040.19950.0221-0.02420.1903-0.00030.178721.1341-20.625327.9516
32.1177-0.15160.04174.54460.34082.2125-0.08170.32640.1088-0.5419-0.11020.2746-0.1196-0.22890.15190.2529-0.0286-0.09210.243-0.0110.211212.8495-29.302218.1288
42.10041.74042.44851.41682.11783.26930.0359-0.15030.0769-0.0748-0.26980.4283-0.0345-0.44990.24060.21460.05990.00150.3195-0.06620.309418.4922-5.11646.8667
52.92410.91340.23462.14780.42782.4816-0.12680.4426-0.0905-0.23680.0341-0.3089-0.15360.39590.07580.1699-0.02110.05180.24680.0330.21190.9364-1.7079-11.706
61.34510.7251-0.07672.60131.36292.30010.0001-0.058-0.0880.0952-0.0899-0.0679-0.01130.12740.08490.1572-0.0165-0.02610.20720.05790.15671.31153.31513.2681
71.8820.5152-0.90074.09721.05121.6026-0.02310.0455-0.10120.1898-0.016-0.80910.07290.32690.03160.2373-0.027-0.02020.24190.0490.3248.88785.37916.0598
81.28461.58990.70173.56420.9991.42890.3246-0.2805-0.16580.7288-0.2589-0.51450.1302-0.01260.00050.26830.0011-0.04470.22190.03750.21674.347312.320714.2644
96.53-0.04470.31832.9767-1.21355.7468-0.1277-0.5758-0.5020.3456-0.011-0.08220.2973-0.00650.09920.2078-0.03230.04020.20990.04470.1695-13.435-11.5796-2.591
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 51 THROUGH 126 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 127 THROUGH 231 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 232 THROUGH 313 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 314 THROUGH 370 )
5X-RAY DIFFRACTION5CHAIN 'B' AND (RESID 50 THROUGH 93 )
6X-RAY DIFFRACTION6CHAIN 'B' AND (RESID 94 THROUGH 171 )
7X-RAY DIFFRACTION7CHAIN 'B' AND (RESID 172 THROUGH 231 )
8X-RAY DIFFRACTION8CHAIN 'B' AND (RESID 232 THROUGH 338 )
9X-RAY DIFFRACTION9CHAIN 'B' AND (RESID 339 THROUGH 367 )

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