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- PDB-4ylj: Crystal structure of DYRK1A in complex with 10-Iodo-substituted 1... -

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Basic information

Entry
Database: PDB / ID: 4ylj
TitleCrystal structure of DYRK1A in complex with 10-Iodo-substituted 11H-indolo[3,2-c]quinoline-6-carboxylic acid inhibitor 5j
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / halogen / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


histone H3T45 kinase activity / positive regulation of protein deacetylation / peptidyl-serine autophosphorylation / negative regulation of DNA methylation-dependent heterochromatin formation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / negative regulation of microtubule polymerization / tau-protein kinase activity / negative regulation of mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator ...histone H3T45 kinase activity / positive regulation of protein deacetylation / peptidyl-serine autophosphorylation / negative regulation of DNA methylation-dependent heterochromatin formation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / negative regulation of microtubule polymerization / tau-protein kinase activity / negative regulation of mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / G0 and Early G1 / peptidyl-tyrosine autophosphorylation / protein serine/threonine/tyrosine kinase activity / cytoskeletal protein binding / tubulin binding / RNA polymerase II CTD heptapeptide repeat kinase activity / positive regulation of RNA splicing / peptidyl-threonine phosphorylation / non-membrane spanning protein tyrosine kinase activity / tau protein binding / circadian rhythm / peptidyl-tyrosine phosphorylation / : / nervous system development / actin binding / peptidyl-serine phosphorylation / protein tyrosine kinase activity / protein autophosphorylation / transcription coactivator activity / cytoskeleton / protein kinase activity / nuclear speck / ribonucleoprotein complex / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4E1 / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsChaikuad, A. / Falke, H. / Nowak, R. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Kunick, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2015
Title: 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A.
Authors: Falke, H. / Chaikuad, A. / Becker, A. / Loaec, N. / Lozach, O. / Abu Jhaisha, S. / Becker, W. / Jones, P.G. / Preu, L. / Baumann, K. / Knapp, S. / Meijer, L. / Kunick, C.
History
DepositionMar 5, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / diffrn_source ...citation / diffrn_source / entity_src_gen / pdbx_struct_assembly / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site ..._citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Sep 27, 2023Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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 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)172,19925
Polymers168,3264
Non-polymers3,87321
Water4,450247
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0506
Polymers42,0821
Non-polymers9695
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)43,4379
Polymers42,0821
Non-polymers1,3558
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)42,7604
Polymers42,0821
Non-polymers6783
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)42,9526
Polymers42,0821
Non-polymers8715
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)265.472, 65.528, 139.365
Angle α, β, γ (deg.)90.00, 114.60, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-603-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALAA135 - 48011 - 356
21VALVALBB135 - 48011 - 356
12VALVALAA135 - 48111 - 357
22VALVALCC135 - 48111 - 357
13VALVALAA135 - 48011 - 356
23VALVALDD135 - 48011 - 356
14VALVALBB135 - 48011 - 356
24VALVALCC135 - 48011 - 356
15LYSLYSBB134 - 48110 - 357
25LYSLYSDD134 - 48110 - 357
16VALVALCC135 - 48011 - 356
26VALVALDD135 - 48011 - 356

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / hMNB


Mass: 42081.535 Da / Num. of mol.: 4 / Fragment: UNP residues 127-485
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)-R3-pRARE2 / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-4E1 / 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid


Mass: 388.159 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H9IN2O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 247 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.27 Å3/Da / Density % sol: 62.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.8
Details: 37% PEG400, 0.2 M lithium sulfate, 0.1 M Tris, pH 8.8

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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: Oct 31, 2013
RadiationMonochromator: Si (111) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.58→48.41 Å / Num. obs: 68848 / % possible obs: 99.6 % / Redundancy: 6.5 % / Biso Wilson estimate: 56.1 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 16.6
Reflection shellResolution: 2.58→2.72 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.884 / Mean I/σ(I) obs: 2.2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata scaling
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2WO6

2wo6


Resolution: 2.58→48.41 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.949 / SU B: 21.661 / SU ML: 0.223 / Cross valid method: THROUGHOUT / ESU R: 0.419 / ESU R Free: 0.25 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22203 3484 5.1 %RANDOM
Rwork0.1919 ---
obs0.19343 65362 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.835 Å2
Baniso -1Baniso -2Baniso -3
1-0.16 Å2-0 Å2-0.54 Å2
2---1.04 Å20 Å2
3---0.96 Å2
Refine analyzeLuzzati coordinate error obs: 0.396 Å
Refinement stepCycle: 1 / Resolution: 2.58→48.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11342 0 222 247 11811
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01912032
X-RAY DIFFRACTIONr_bond_other_d0.0050.0211449
X-RAY DIFFRACTIONr_angle_refined_deg1.4122.00116256
X-RAY DIFFRACTIONr_angle_other_deg0.853326342
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.21651410
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.78523.812564
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.744152132
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0011578
X-RAY DIFFRACTIONr_chiral_restr0.0650.21684
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02113328
X-RAY DIFFRACTIONr_gen_planes_other0.0050.022864
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_it3.0344.2515580
X-RAY DIFFRACTIONr_mcbond_other3.0344.2525581
X-RAY DIFFRACTIONr_mcangle_it4.7996.3726974
X-RAY DIFFRACTIONr_mcangle_other4.7996.3736975
X-RAY DIFFRACTIONr_scbond_it3.7124.7936452
X-RAY DIFFRACTIONr_scbond_other3.7124.7946453
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.7297.029271
X-RAY DIFFRACTIONr_long_range_B_refined8.55237.85214269
X-RAY DIFFRACTIONr_long_range_B_other8.55137.85614270
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A226270.05
12B226270.05
21A227660.03
22C227660.03
31A227420.04
32D227420.04
41B226050.05
42C226050.05
51B226180.05
52D226180.05
61C227960.03
62D227960.03
LS refinement shellResolution: 2.58→2.647 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.422 250 -
Rwork0.346 4811 -
obs--99.9 %
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)
11.9091-0.2046-0.02282.81870.96762.23690.0955-0.34910.01570.03230.2481-0.3551-0.31330.3425-0.34360.463-0.2130.00910.3431-0.10770.091111.667815.977932.1577
20.83160.17750.06070.50510.09941.00150.1893-0.0191-0.03570.169-0.07030.056-0.0127-0.0371-0.1190.4124-0.04910.00790.25460.01290.1287-5.99844.832515.4129
32.8323-0.44191.71021.3775-0.63631.16830.26990.1222-0.4328-0.1408-0.01470.08340.1493-0.0419-0.25520.27090.0517-0.01270.4939-0.09450.0928-49.0043-16.3372-7.2712
42.3638-0.18810.23721.80250.15970.84580.2467-0.17180.01510.2457-0.1824-0.1109-0.0089-0.1486-0.06430.3152-0.09010.0240.38210.02040.1325-32.9482-5.966712.5669
50.8865-0.6776-0.32481.22041.31653.67720.023-0.19680.1297-0.53040.2566-0.3021-1.1889-0.4008-0.27961.1281-0.0460.08280.2847-0.07930.08490.7053-23.226545.0432
60.2371-0.48980.56541.2996-0.68445.1132-0.0278-0.18690.0742-0.1692-0.0113-0.1866-0.5511-1.48990.03910.48450.16680.01640.8546-0.05810.0584-11.5816-25.692369.3599
72.5180.64780.07231.11810.65031.46380.20520.4419-0.20820.17710.0239-0.1026-0.0696-0.0081-0.22910.2824-0.0413-0.06140.53660.14380.137-61.1857-29.708717.3648
80.74740.19670.82861.51820.20333.5742-0.10810.03210.08490.3040.15430.1961-0.6278-0.4102-0.04610.41410.11040.11170.35230.18880.1329-68.9957-14.058541.1826
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A135 - 219
2X-RAY DIFFRACTION2A220 - 481
3X-RAY DIFFRACTION3B134 - 313
4X-RAY DIFFRACTION4B314 - 481
5X-RAY DIFFRACTION5C135 - 313
6X-RAY DIFFRACTION6C314 - 481
7X-RAY DIFFRACTION7D134 - 243
8X-RAY DIFFRACTION8D244 - 481

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