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- PDB-6eij: DYRK1A in complex with HG-8-60-1 -

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Basic information

Entry
Database: PDB / ID: 6eij
TitleDYRK1A in complex with HG-8-60-1
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Function / homology
Function and homology information


regulation of amyloid-beta formation / negative regulation of heterochromatin formation / regulation of neurofibrillary tangle assembly / histone H3T45 kinase activity / dual-specificity kinase / splicing factor binding / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / regulation of alternative mRNA splicing, via spliceosome / negative regulation of microtubule polymerization ...regulation of amyloid-beta formation / negative regulation of heterochromatin formation / regulation of neurofibrillary tangle assembly / histone H3T45 kinase activity / dual-specificity kinase / splicing factor binding / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / regulation of alternative mRNA splicing, via spliceosome / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 / cytoskeletal protein binding / protein serine/threonine/tyrosine kinase activity / RNA polymerase II CTD heptapeptide repeat kinase activity / tubulin binding / peptidyl-tyrosine phosphorylation / positive regulation of RNA splicing / non-membrane spanning protein tyrosine kinase activity / circadian rhythm / tau protein binding / nervous system development / protein autophosphorylation / actin binding / protein tyrosine kinase activity / transcription coactivator activity / protein phosphorylation / protein kinase activity / nuclear speck / ribonucleoprotein complex / axon / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / centrosome / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / 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. ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / 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-B5Z / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsRothweiler, U.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors.
Authors: Czarna, A. / Wang, J. / Zelencova, D. / Liu, Y. / Deng, X. / Choi, H.G. / Zhang, T. / Zhou, W. / Chang, J.W. / Kildalsen, H. / Seternes, O.M. / Gray, N.S. / Engh, R.A. / Rothweiler, U.
History
DepositionSep 19, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)172,4828
Polymers170,6164
Non-polymers1,8664
Water6,323351
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1212
Polymers42,6541
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1212
Polymers42,6541
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1212
Polymers42,6541
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1212
Polymers42,6541
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.240, 88.040, 228.500
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Dual specificity tyrosine-phosphorylation-regulated kinase 1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog


Mass: 42653.992 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A,DYRK,MNB,MNBH / Production host: Escherichia coli (E. coli) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-B5Z / ~{N}-[5-[3-(2-morpholin-4-ylethylcarbamoylamino)phenyl]-[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide


Mass: 466.556 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H26N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 351 / 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: 2.63 Å3/Da / Density % sol: 53.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M KSCN; 0.05M KCl; 10% PEG 3350, pH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.984003 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.984003 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.823
11K, H, -L20.177
ReflectionResolution: 2.45→50 Å / Num. obs: 66317 / % possible obs: 99.2 % / Redundancy: 6.4 % / CC1/2: 0.997 / Rrim(I) all: 0.107 / Net I/σ(I): 14.24
Reflection shell

Diffraction-ID: 1

Resolution (Å)Mean I/σ(I) obsNum. measured obsNum. unique allNum. unique obsCC1/2Rrim(I) all% possible all
2.45-2.62.476537110626101670.8370.68895.7
2.6-2.7846819810029100230.9280.44899.9
2.78-35.860102935793520.9620.30499.9
3-3.299.9857315863486280.9840.18299.9
3.29-3.6716.8851848785578480.9930.11299.9
3.67-4.2424.541928695369410.9950.07699.8
4.24-5.1831.5836455594759390.9970.06199.9
5.18-7.2830.9127373467346650.9970.05899.8
7.28-5038.0215881277627540.9980.04499.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4nct

4nct


Resolution: 2.42→48.4 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.913 / SU B: 16.622 / SU ML: 0.201 / Cross valid method: THROUGHOUT / ESU R: 0.093 / ESU R Free: 0.055 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24192 3302 5 %RANDOM
Rwork0.21341 ---
obs0.21485 63007 95.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 50.255 Å2
Baniso -1Baniso -2Baniso -3
1-16.81 Å20 Å20 Å2
2--5.48 Å20 Å2
3----22.3 Å2
Refinement stepCycle: 1 / Resolution: 2.42→48.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11006 0 132 351 11489
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01911416
X-RAY DIFFRACTIONr_bond_other_d0.0040.0210863
X-RAY DIFFRACTIONr_angle_refined_deg1.2371.98215440
X-RAY DIFFRACTIONr_angle_other_deg0.9773.00524957
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7151350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.99424.011536
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.877151980
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7141565
X-RAY DIFFRACTIONr_chiral_restr0.0680.21641
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02112771
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022710
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_it0.8353.8995427
X-RAY DIFFRACTIONr_mcbond_other0.8353.8995426
X-RAY DIFFRACTIONr_mcangle_it1.4715.8426768
X-RAY DIFFRACTIONr_mcangle_other1.4715.8426769
X-RAY DIFFRACTIONr_scbond_it0.6773.9575989
X-RAY DIFFRACTIONr_scbond_other0.6773.9585990
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.195.9148661
X-RAY DIFFRACTIONr_long_range_B_refined3.29444.93112854
X-RAY DIFFRACTIONr_long_range_B_other3.20544.81312795
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.424→2.487 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 98 -
Rwork0.291 1984 -
obs--41.25 %
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)
10.18360.2652-0.12040.4231-0.12230.4151-0.0157-0.007-0.0382-0.01350.0144-0.0208-0.01390.00170.00140.11240.0114-0.01470.02870.00140.159-5.5281-21.91649.1333
20.13420.0633-0.27870.2656-0.04690.8660.0319-0.0311-0.0177-0.10560.04130.0037-0.10710.1042-0.07320.2145-0.04060.0370.0426-0.02720.0967-1.0981-19.3858.3252
30.1440.00510.02220.5471-0.08350.6314-0.1228-0.0179-0.0313-0.19750.156-0.0414-0.11020.0717-0.03320.256-0.06410.01120.0707-0.03480.1134-12.562617.646819.3245
40.17050.0112-0.06820.2009-0.24741.2075-0.0435-0.0432-0.0357-0.04750.10830.0614-0.0724-0.1169-0.06470.1250.0082-0.05180.08170.01480.1159-40.205-5.697137.9775
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A134 - 480
2X-RAY DIFFRACTION2B133 - 480
3X-RAY DIFFRACTION3C135 - 479
4X-RAY DIFFRACTION4D134 - 479

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