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- PDB-8uok: Crystal structure of human NUAK1-MARK3 (7 mutations) kinase domai... -

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Basic information

Entry
Database: PDB / ID: 8uok
TitleCrystal structure of human NUAK1-MARK3 (7 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


negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / regulation of G2/M transition of mitotic cell cycle / 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 / Negative regulation of MAPK pathway ...negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / regulation of G2/M transition of mitotic cell cycle / 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 / Negative regulation of MAPK pathway / microtubule cytoskeleton organization / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / protein phosphatase binding / protein phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / 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: 1.85 Å
AuthorsDelker, S.L. / Abendroth, J. / Fox III, D.D.
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 1.1Dec 11, 2024Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 25, 2024Group: 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

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)77,00112
Polymers75,8062
Non-polymers1,19510
Water11,043613
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.970, 106.190, 84.380
Angle α, β, γ (deg.)90.00, 132.38, 90.00
Int Tables number5
Space group name H-MC121

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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.: 2 / 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-X5N / (6P)-6-[(4R)-imidazo[1,2-a]pyridin-3-yl]-4-(piperidin-4-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one


Mass: 349.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 613 / 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: 2.64 Å3/Da / Density % sol: 53.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 318327A2 (JCSG E10 FS), 100mM Bicine, pH 8.3, PEG 6000 10.6 %w/v with 2.5mM compound, 25% EG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.978 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Nov 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.85→42.17 Å / Num. obs: 65874 / % possible obs: 97.6 % / Redundancy: 3.3 % / CC1/2: 0.998 / Rmerge(I) obs: 4.2 / Net I/σ(I): 16.79
Reflection shellResolution: 1.85→1.9 Å / Num. unique obs: 4196 / CC1/2: 0.922

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIXDEV_3374refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UCB MODEL

Resolution: 1.85→42.17 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.192 1933 2.94 %
Rwork0.159 --
obs0.16 65860 98.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.33 Å2
Refinement stepCycle: LAST / Resolution: 1.85→42.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms0 5198 84 613 5895
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d05555
X-RAY DIFFRACTIONf_angle_d0.777495
X-RAY DIFFRACTIONf_dihedral_angle_d14.423470
X-RAY DIFFRACTIONf_chiral_restr0.05817
X-RAY DIFFRACTIONf_plane_restr0950
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.89630.32011370.26573892X-RAY DIFFRACTION84
1.8963-1.94750.29191350.21564424X-RAY DIFFRACTION96
1.9475-2.00490.23121550.1864558X-RAY DIFFRACTION98
2.0049-2.06960.23831300.17144594X-RAY DIFFRACTION100
2.0696-2.14350.19551260.16074634X-RAY DIFFRACTION100
2.1435-2.22930.20771370.16064636X-RAY DIFFRACTION100
2.2293-2.33080.18611150.15754660X-RAY DIFFRACTION100
2.3308-2.45370.19921200.16224620X-RAY DIFFRACTION100
2.4537-2.60740.23231410.16694645X-RAY DIFFRACTION100
2.6074-2.80870.17271530.16554641X-RAY DIFFRACTION100
2.8087-3.09120.19981280.1684679X-RAY DIFFRACTION100
3.0912-3.53830.19221690.15494594X-RAY DIFFRACTION100
3.5383-4.45720.17321450.13194660X-RAY DIFFRACTION100
4.4572-42.170.15221420.15174690X-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)
16.57620.12570.30452.8918-0.82253.90990.14210.51530.3096-0.52720.1374-0.0414-0.3730.0145-0.11740.30140.06930.02260.17140.06520.24472.646666.881922.4629
21.0288-0.9197-0.79431.83150.48611.6336-0.03780.05020.134-0.0454-0.00210.1557-0.0592-0.19660.02010.15720.0096-0.00770.16020.01330.1767.655550.313825.484
33.2017-0.0119-0.34511.91760.55453.2908-0.11590.1815-0.2116-0.0612-0.00530.19570.1394-0.24810.06520.1496-0.00640.02940.1251-0.01340.179614.287634.813817.8418
42.2281-3.8418-1.01417.32791.89580.1818-0.4704-0.38640.10140.80870.4699-0.12190.18540.18360.04290.37530.08350.01360.2935-0.01740.20075.829661.932342.8219
53.5109-0.23880.15773.6146-0.45985.8721-0.30240.0669-0.50820.06870.20890.63080.3578-0.5802-0.01520.2255-0.07140.00280.1957-0.01370.315422.175663.99691.3354
61.0562-0.2466-0.33692.45921.09521.29370.05520.1179-0.0037-0.06290.05590.12520.088-0.0291-0.10280.1536-0.00520.00260.15460.00290.167424.872781.03675.6017
72.8574-0.55070.09562.3341-0.30453.65880.04580.13450.0785-0.09640.03540.1136-0.1085-0.122-0.07210.1871-0.00780.04740.1162-0.00550.161817.239396.576612.8157
80.423-2.7224-1.50527.42873.98412.34680.0084-0.17820.279-0.03260.4815-0.80720.02020.2748-0.48020.18060.0059-0.00910.2888-0.07180.344742.501769.88492.7831
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 51 THROUGH 93 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 94 THROUGH 209 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 210 THROUGH 313 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 314 THROUGH 369 )
5X-RAY DIFFRACTION5CHAIN 'B' AND (RESID 51 THROUGH 93 )
6X-RAY DIFFRACTION6CHAIN 'B' AND (RESID 94 THROUGH 209 )
7X-RAY DIFFRACTION7CHAIN 'B' AND (RESID 210 THROUGH 313 )
8X-RAY DIFFRACTION8CHAIN 'B' AND (RESID 314 THROUGH 369 )

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