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- PDB-5lxd: Crystal structure of DYRK2 in complex with EHT 1610 (compound 2) -

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Basic information

Entry
Database: PDB / ID: 5lxd
TitleCrystal structure of DYRK2 in complex with EHT 1610 (compound 2)
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 / positive regulation of glycogen biosynthetic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / manganese ion binding / protein tyrosine kinase activity ...dual-specificity kinase / negative regulation of calcineurin-NFAT signaling cascade / smoothened signaling pathway / positive regulation of glycogen biosynthetic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / manganese ion binding / protein tyrosine kinase activity / Regulation of TP53 Activity through Phosphorylation / cytoskeleton / ribonucleoprotein complex / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / magnesium ion binding / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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. ...Dual specificity tyrosine-phosphorylation-regulated kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7A7 / Dual specificity tyrosine-phosphorylation-regulated kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)95,32614
Polymers93,9392
Non-polymers1,38712
Water3,477193
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6637
Polymers46,9691
Non-polymers6946
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)47,6637
Polymers46,9691
Non-polymers6946
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.240, 130.000, 136.330
Angle α, β, γ (deg.)90.00, 90.40, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B
13A
23B
14A
24B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A81 - 110
2112B81 - 110
1212A111 - 144
2212B111 - 144
1122A145 - 390
2122B145 - 390
1132A391 - 420
2132B391 - 420
1142A421 - 465
2142B421 - 465

NCS ensembles :
ID
1
2
3
4

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.999863, 0.001153, 0.016514), (0.001202, -0.999995, -0.002972), (0.016511, 0.002992, -0.999859)-0.78145, -5.30909, 67.851501
3given(1), (1), (1)
4given(0.999996, 0.00286, 0.000148), (0.00286, -0.999994, -0.002175), (0.000141, 0.002175, -0.999998)0.05665, -5.44937, 68.87262
5given(1), (1), (1)
6given(0.999981, 0.005646, 0.002275), (0.005664, -0.999951, -0.00814), (0.002229, 0.008153, -0.999964)0.01857, -5.52643, 68.653282
7given(1), (1), (1)
8given(0.99999, -0.002367, -0.003707), (-0.002367, -0.999997, -9.0E-6), (-0.003707, 1.7E-5, -0.999993)0.05027, -5.12866, 69.094093

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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-7A7 / methyl 9-[(2-fluoranyl-4-methoxy-phenyl)amino]-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate


Mass: 383.399 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H14FN5O2S
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O

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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: 3.12 Å3/Da / Density % sol: 60.63 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 1.5 M Li2SO4 and 0.1 M HEPES, pH 7.5

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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: 2.58→47.04 Å / Num. obs: 35477 / % possible obs: 97.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 44.6 Å2 / Rmerge(I) obs: 0.091 / Net I/σ(I): 9.1
Reflection shellResolution: 2.58→2.72 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.649 / Mean I/σ(I) obs: 2 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.58→47.04 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.92 / SU B: 23.618 / SU ML: 0.255 / Cross valid method: THROUGHOUT / ESU R: 0.486 / ESU R Free: 0.295 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25303 1773 5 %RANDOM
Rwork0.1971 ---
obs0.19982 33703 97.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 66.994 Å2
Baniso -1Baniso -2Baniso -3
1--1.64 Å2-0 Å20.51 Å2
2---4.99 Å2-0 Å2
3---6.63 Å2
Refine analyzeLuzzati coordinate error obs: 0.381 Å
Refinement stepCycle: 1 / Resolution: 2.58→47.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6223 0 94 193 6510
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0196503
X-RAY DIFFRACTIONr_bond_other_d0.0010.026236
X-RAY DIFFRACTIONr_angle_refined_deg1.1791.9798759
X-RAY DIFFRACTIONr_angle_other_deg0.6783.00214333
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.25782
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.60823.377308
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.184151157
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3441550
X-RAY DIFFRACTIONr_chiral_restr0.0750.2906
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217300
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021564
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_it1.8323.4013098
X-RAY DIFFRACTIONr_mcbond_other1.8323.43097
X-RAY DIFFRACTIONr_mcangle_it2.9875.0993872
X-RAY DIFFRACTIONr_mcangle_other2.9875.0993873
X-RAY DIFFRACTIONr_scbond_it2.0293.6773404
X-RAY DIFFRACTIONr_scbond_other2.0263.6773404
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.3225.4024881
X-RAY DIFFRACTIONr_long_range_B_refined5.37527.5827512
X-RAY DIFFRACTIONr_long_range_B_other5.37527.5877513
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
1594MEDIUM POSITIONAL0.010.5
1373TIGHT THERMAL2.140.5
1594MEDIUM THERMAL2.372
22601MEDIUM POSITIONAL0.020.5
21457TIGHT THERMAL1.970.5
22601MEDIUM THERMAL2.422
3263MEDIUM POSITIONAL0.010.5
3173TIGHT THERMAL1.470.5
3263MEDIUM THERMAL1.452
4464MEDIUM POSITIONAL0.020.5
4265TIGHT THERMAL1.190.5
4464MEDIUM THERMAL1.762
LS refinement shellResolution: 2.58→2.647 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.398 112 -
Rwork0.324 2518 -
obs--99.4 %
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)
14.59021.25822.55450.99990.56281.9611-0.05250.4035-0.0559-0.34240.07870.38850.0805-0.0784-0.02620.27170.0338-0.0940.2462-0.0330.363458.273713.494516.3099
24.213-0.75130.10816.0962-0.79632.908-0.1809-0.5701-0.20660.71090.0594-0.03150.0957-0.04980.12150.14090.0241-0.00880.1224-0.01580.059477.574112.288443.0839
34.3928-0.0265-1.91112.6993-0.1541.61080.2125-0.40890.48010.7543-0.03470.8101-0.197-0.1107-0.17780.3562-0.05250.17810.1795-0.06390.339558.2196-18.899352.4376
44.50991.3401-0.89776.216-1.08533.0664-0.16720.60540.2165-0.69890.0916-0.2921-0.0731-0.18270.07560.12480.00680.01390.126-0.00890.075677.5653-17.564625.7298
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A80 - 304
2X-RAY DIFFRACTION2A305 - 465
3X-RAY DIFFRACTION3B80 - 304
4X-RAY DIFFRACTION4B305 - 465

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