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

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Basic information

Entry
Database: PDB / ID: 8uoj
TitleCrystal structure of human NUAK1-MARK3 kinase domain chimera bound with azepane (R)-#50 small molecule inhibitor
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
BENZOIC ACID / : / MAP/microtubule affinity-regulating kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsDelker, S.L. / Abendroth, J. / Mayclin, S.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 1.0Nov 6, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7949
Polymers37,9491
Non-polymers8458
Water7,494416
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.350, 115.490, 161.820
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-408-

BEZ

21A-408-

BEZ

31A-408-

BEZ

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Components

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Protein , 1 types, 1 molecules A

#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: 37948.910 Da / Num. of mol.: 1 / Mutation: I62L, V116I, G137K, F141Y, A146E, L72R
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

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Non-polymers , 5 types, 424 molecules

#2: Chemical ChemComp-X5I / (6M)-4-{[(2R)-azepan-2-yl]methyl}-6-[(4R)-imidazo[1,2-a]pyridin-3-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one


Mass: 377.440 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-BEZ / BENZOIC ACID


Mass: 122.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 416 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.8 Å3/Da / Density % sol: 56.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100mM Tris base / HCl pH 7.5, 200mM Magnesium chloride, 10% (w/V) PEG8000; 2.5mM UCB1718758 (bsi109321)

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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: Feb 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9749 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 56580 / % possible obs: 100 % / Redundancy: 6.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.053 / Rrim(I) all: 0.058 / Net I/σ(I): 17.16
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.6-1.640.51141190.8770.5841
1.64-1.690.40740170.9380.4511
1.69-1.740.33239400.9710.3621
1.74-1.790.27238040.9770.2961
1.79-1.850.20936820.9870.2281
1.85-1.910.16836000.990.1831
1.91-1.980.1334660.9940.1411
1.98-2.070.10733390.9950.1161
2.07-2.160.08632100.9960.0931
2.16-2.260.07330550.9970.0791
2.26-2.390.06629140.9970.0721
2.39-2.530.06127600.9970.0671
2.53-2.70.05626090.9980.0611
2.7-2.920.0524330.9980.0551
2.92-3.20.04622560.9980.051
3.2-3.580.04420400.9980.0471
3.58-4.130.0418330.9980.0441
4.13-5.060.03915540.9990.0421
5.06-7.160.04112200.9980.0441
7.16-500.0477290.9970.0521

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Processing

Software
NameVersionClassification
PHENIXDEV_3409refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UCB MODEL

Resolution: 1.6→48.87 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.186 2068 3.66 %
Rwork0.159 --
obs0.16 56557 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.79 Å2
Refinement stepCycle: LAST / Resolution: 1.6→48.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms0 2616 62 416 3094
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d02839
X-RAY DIFFRACTIONf_angle_d0.933836
X-RAY DIFFRACTIONf_dihedral_angle_d16.41767
X-RAY DIFFRACTIONf_chiral_restr0.06419
X-RAY DIFFRACTIONf_plane_restr0488
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.63720.26731460.24833550X-RAY DIFFRACTION100
1.6372-1.67820.25551500.21933599X-RAY DIFFRACTION100
1.6782-1.72350.2341380.20123565X-RAY DIFFRACTION100
1.7235-1.77430.23081330.1843592X-RAY DIFFRACTION100
1.7743-1.83150.21491430.18343578X-RAY DIFFRACTION100
1.8315-1.8970.2021260.17833616X-RAY DIFFRACTION100
1.897-1.9730.20731370.16773627X-RAY DIFFRACTION100
1.973-2.06270.20221400.16593586X-RAY DIFFRACTION100
2.0627-2.17150.18481340.16263611X-RAY DIFFRACTION100
2.1715-2.30750.21461360.16023621X-RAY DIFFRACTION100
2.3075-2.48570.2181320.1653657X-RAY DIFFRACTION100
2.4857-2.73580.19291290.16633651X-RAY DIFFRACTION100
2.7358-3.13170.17161360.15863652X-RAY DIFFRACTION100
3.1317-3.94530.15651480.14083704X-RAY DIFFRACTION100
3.9453-48.870.16431400.14573880X-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)
11.9992-1.10741.06282.7693-0.92373.0924-0.0695-0.2918-0.16250.19610.26370.39630.1825-0.6255-0.20280.1986-0.0450.0030.31270.06490.2634-16.3724-44.0628-14.4248
21.3521-0.24990.2221.8597-0.35362.13980.04950.0759-0.1555-0.11470.00910.07050.2084-0.2392-0.05820.1722-0.0162-0.01250.18290.01390.1814-8.2621-43.1836-22.2032
30.78810.2364-0.00793.0167-0.8121.10520.0373-0.09140.07580.1971-0.02820.0755-0.0766-0.06510.00370.1840.0040.00190.20490.00920.1578-6.9547-25.0006-21.1953
42.90460.66582.14214.392-1.24184.26530.13320.14760.0172-0.2390.00360.3421-0.0348-0.1957-0.13180.17950.0126-0.00490.21340.01270.1793-14.6502-32.6698-31.1856
55.7433-0.67920.60844.3848-2.18321.6392-0.03610.5024-0.1955-0.3617-0.0056-0.02130.29610.0040.05880.1967-0.0180.00290.17480.01790.1586-9.1739-20.3617-35.9617
63.31252.66372.54574.10981.68764.4656-0.0937-0.0460.3531-0.2031-0.02120.3623-0.2028-0.44820.13910.18180.0364-0.00330.18090.02930.2092-13.4904-10.6663-34.0135
70.2811-0.75830.4823.9002-3.08252.4773-0.03140.02070.15290.0678-0.2472-0.5523-0.01150.20840.31450.1758-0.00670.01160.23040.01070.29556.4337-24.3256-22.0431
83.04110.97870.99535.7641-1.2776.55820.02770.1258-0.0435-0.19510.0832-0.13480.23410.0506-0.0520.19130.0048-0.02480.21940.00960.18243.7162-46.2285-11.1214
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 50 THROUGH 67 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 68 THROUGH 126 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 127 THROUGH 194 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 195 THROUGH 215 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 216 THROUGH 248 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 249 THROUGH 287 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 288 THROUGH 337 )
8X-RAY DIFFRACTION8CHAIN 'A' AND (RESID 338 THROUGH 370 )

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