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- PDB-5lxc: Crystal structure of DYRK2 in complex with EHT 5372 (Compound 1) -

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Basic information

Entry
Database: PDB / ID: 5lxc
TitleCrystal structure of DYRK2 in complex with EHT 5372 (Compound 1)
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 2
KeywordsTRANSFERASE / kinase / inhibitor / unusual binding mode / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


dual-specificity kinase / negative regulation of calcineurin-NFAT signaling cascade / smoothened signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of glycogen biosynthetic process / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / histone H2AXY142 kinase activity / manganese ion binding ...dual-specificity kinase / negative regulation of calcineurin-NFAT signaling cascade / smoothened signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of glycogen biosynthetic process / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / histone H2AXY142 kinase activity / manganese ion binding / histone H3Y41 kinase activity / protein tyrosine kinase activity / Regulation of TP53 Activity through Phosphorylation / cytoskeleton / ribonucleoprotein complex / protein phosphorylation / protein serine/threonine kinase activity / protein serine kinase activity / DNA damage response / magnesium ion binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. ...Dual specificity tyrosine-phosphorylation-regulated kinase / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7AA / Dual specificity tyrosine-phosphorylation-regulated kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsChaikuad, A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A. / Bountra, C. / Besson, T. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J. Med. Chem. / Year: 2016
Title: An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases.
Authors: Chaikuad, A. / Diharce, J. / Schroder, M. / Foucourt, A. / Leblond, B. / Casagrande, A.S. / Desire, L. / Bonnet, P. / Knapp, S. / Besson, T.
History
DepositionSep 20, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 26, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2017Group: Database references
Revision 1.2Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual specificity tyrosine-phosphorylation-regulated kinase 2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,43015
Polymers93,9392
Non-polymers1,49113
Water7,134396
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,87010
Polymers46,9691
Non-polymers9019
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5605
Polymers46,9691
Non-polymers5904
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)130.220, 60.980, 148.790
Angle α, β, γ (deg.)90.00, 105.04, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-687-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B
13B
23A
14B
24A

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A81 - 110
2112B81 - 110
1214A111 - 144
2214B111 - 144
1122A145 - 390
2122B145 - 390
1134B391 - 420
2134A391 - 420
1142B421 - 464
2142A421 - 464

NCS ensembles :
ID
1
2
3
4

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.020111, 0.509966, -0.859959), (0.677581, -0.625523, -0.386788), (-0.735173, -0.59047, -0.332964)81.692833, -9.08403, 90.697693
3given(1), (1), (1)
4given(0.009743, 0.568123, -0.822886), (0.637234, -0.637711, -0.432732), (-0.770608, -0.520155, -0.368241)77.363777, -3.67951, 94.869568
5given(1), (1), (1)
6given(-0.028827, 0.631161, -0.775116), (0.574354, -0.624191, -0.529626), (-0.8181, -0.460458, -0.344516)77.39283, 2.9148, 96.982986
7given(1), (1), (1)
8given(0.005589, 0.633686, -0.77357), (0.573182, -0.63592, -0.516786), (-0.819409, -0.440508, -0.366772)75.005257, 2.64265, 97.018356

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Components

#1: Protein Dual specificity tyrosine-phosphorylation-regulated kinase 2


Mass: 46969.293 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK2 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): R3-pRARE2 / References: UniProt: Q92630, dual-specificity kinase
#2: Chemical ChemComp-7AA / methyl 9-[(2,4-dichlorophenyl)amino]-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate


Mass: 404.273 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H11Cl2N5OS
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 396 / Source method: isolated from a natural source / Formula: H2O
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: 3.04 Å3/Da / Density % sol: 59.5 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% PEG 3350, 0.2 M NaCl and 0.1 M bis-tris, pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Dec 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.15→49.43 Å / Num. obs: 60094 / % possible obs: 97.6 % / Redundancy: 4 % / Biso Wilson estimate: 26.4 Å2 / Rmerge(I) obs: 0.107 / Net I/σ(I): 8.2
Reflection shellResolution: 2.15→2.27 Å / Redundancy: 4 % / Rmerge(I) obs: 0.578 / Mean I/σ(I) obs: 2.1 / % possible all: 98.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→49.43 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.914 / SU B: 13.049 / SU ML: 0.172 / Cross valid method: THROUGHOUT / ESU R: 0.215 / ESU R Free: 0.193 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25401 3047 5.1 %RANDOM
Rwork0.20564 ---
obs0.20808 57045 97.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 49.867 Å2
Baniso -1Baniso -2Baniso -3
1--1.8 Å20 Å21.67 Å2
2---2.92 Å2-0 Å2
3---3.73 Å2
Refine analyzeLuzzati coordinate error obs: 0.318 Å
Refinement stepCycle: 1 / Resolution: 2.15→49.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6215 0 96 396 6707
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0196520
X-RAY DIFFRACTIONr_bond_other_d0.0040.026263
X-RAY DIFFRACTIONr_angle_refined_deg1.4431.9788784
X-RAY DIFFRACTIONr_angle_other_deg0.8233.00114400
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2435788
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.02823.269309
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.797151167
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9181552
X-RAY DIFFRACTIONr_chiral_restr0.0820.2908
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0217322
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021576
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.642.4013098
X-RAY DIFFRACTIONr_mcbond_other1.6392.4013097
X-RAY DIFFRACTIONr_mcangle_it2.5263.5963874
X-RAY DIFFRACTIONr_mcangle_other2.5253.5963875
X-RAY DIFFRACTIONr_scbond_it2.142.6743422
X-RAY DIFFRACTIONr_scbond_other2.1362.6743422
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.3153.8974901
X-RAY DIFFRACTIONr_long_range_B_refined5.95920.2657751
X-RAY DIFFRACTIONr_long_range_B_other5.95920.2717752
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A788MEDIUM POSITIONAL0.350.5
1A178TIGHT THERMAL1.580.5
1A788MEDIUM THERMAL2.512
2A2537MEDIUM POSITIONAL0.050.5
2A1447TIGHT THERMAL2.060.5
2A2537MEDIUM THERMAL3.242
3B421MEDIUM POSITIONAL0.340.5
3B421MEDIUM THERMAL3.822
4B420MEDIUM POSITIONAL0.140.5
4B249TIGHT THERMAL1.930.5
4B420MEDIUM THERMAL2.342
LS refinement shellResolution: 2.15→2.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 220 -
Rwork0.305 4278 -
obs--98.86 %
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)
15.3451.8306-0.12748.8679-1.12672.7516-0.18530.1281-0.373-0.35950.1768-0.4880.2359-0.04260.00850.1063-0.02080.0280.02230.01420.098233.3243-8.363816.3025
24.56921.8511-0.35783.7181-0.00531.2309-0.0765-0.12090.1158-0.13980.05110.01960.1726-0.06450.02540.06570.0066-0.02090.0285-0.00250.067341.367517.609617.8013
33.8844-0.20291.13682.1533-0.1591.6564-0.161-0.35520.68720.1939-0.056-0.1371-0.23370.13390.2170.0699-0.0118-0.03130.0831-0.06360.312960.385232.644828.1881
44.1006-0.2859-0.2991.43050.14864.85080.3053-0.47920.5540.0613-0.06310.039-0.5944-0.1742-0.24220.6212-0.00030.35650.6478-0.01980.53356.848318.532964.8652
56.481-1.124-4.54335.73461.89443.5790.2785-0.20660.10580.2671-0.11220.2928-0.0793-0.1595-0.16630.4335-0.04570.11960.58560.16660.227966.95035.615555.725
62.4338-0.12750.25341.909-0.3422.6686-0.0204-0.2793-0.17770.01570.01340.0090.1585-0.0310.0070.02970.0110.02790.03820.02710.055375.95613.199129.7048
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A80 - 154
2X-RAY DIFFRACTION2A155 - 307
3X-RAY DIFFRACTION3A308 - 464
4X-RAY DIFFRACTION4B80 - 161
5X-RAY DIFFRACTION5B162 - 230
6X-RAY DIFFRACTION6B231 - 465

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