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- PDB-4yll: Crystal structure of DYRK1AA in complex with 10-Bromo-substituted... -

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Basic information

Entry
Database: PDB / ID: 4yll
TitleCrystal structure of DYRK1AA in complex with 10-Bromo-substituted 11H-indolo[3,2-c]quinolone-6-carboxylic acid inhibitor 5t
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / halogen / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / actin binding / protein autophosphorylation / 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 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4E3 / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsChaikuad, A. / Falke, H. / Krojer, T. / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
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
Revision 1.5Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,58816
Polymers42,0821
Non-polymers1,50615
Water10,395577
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)100.030, 69.860, 67.900
Angle α, β, γ (deg.)90.00, 117.72, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-611-

HOH

21A-735-

HOH

31A-748-

HOH

41A-784-

HOH

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Components

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


Mass: 42081.535 Da / Num. of mol.: 1 / 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-4E3 / 10-bromo-2-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid


Mass: 467.055 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H8BrIN2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 577 / 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

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 50.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 2 M ammonium sulfate, 0.1 M citrate, pH 5.6, 0.2 M potassium/sodium tartrate

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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: Jul 13, 2012
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: 1.4→28.21 Å / Num. obs: 77083 / % possible obs: 95 % / Redundancy: 3.3 % / Biso Wilson estimate: 10.8 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 12.4
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.268 / Mean I/σ(I) obs: 4.4 / % possible all: 95.4

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Processing

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

2wo6


Resolution: 1.4→27.42 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.601 / SU ML: 0.034 / Cross valid method: THROUGHOUT / ESU R: 0.053 / ESU R Free: 0.055 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17163 3859 5 %RANDOM
Rwork0.15053 ---
obs0.15161 73218 94.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.565 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å2-0 Å2-0.35 Å2
2--0.06 Å2-0 Å2
3---0.24 Å2
Refine analyzeLuzzati coordinate error obs: 0.144 Å
Refinement stepCycle: 1 / Resolution: 1.4→27.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2783 0 83 577 3443
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0193003
X-RAY DIFFRACTIONr_bond_other_d0.0010.022873
X-RAY DIFFRACTIONr_angle_refined_deg1.6671.9924059
X-RAY DIFFRACTIONr_angle_other_deg0.77136619
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0085366
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.01324.014142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.94215536
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4421518
X-RAY DIFFRACTIONr_chiral_restr0.0940.2428
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213335
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02707
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_it0.5070.5061392
X-RAY DIFFRACTIONr_mcbond_other0.5010.5051391
X-RAY DIFFRACTIONr_mcangle_it0.8530.7551743
X-RAY DIFFRACTIONr_mcangle_other0.8540.7571744
X-RAY DIFFRACTIONr_scbond_it0.8660.6361610
X-RAY DIFFRACTIONr_scbond_other0.8650.6361611
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.3050.9042304
X-RAY DIFFRACTIONr_long_range_B_refined5.2777.3824126
X-RAY DIFFRACTIONr_long_range_B_other5.2767.3824127
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded2.69851
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.191 296 -
Rwork0.19 5365 -
obs--95.09 %
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)
11.50530.6075-0.49811.3842-0.62242.1734-0.0132-0.0688-0.15090.0701-0.0039-0.1170.20120.11020.0170.03250.0125-0.00840.0211-0.00130.020925.952147.879943.3163
26.92672.99113.4622.39641.7454.9354-0.2578-0.91980.51670.301-0.08810.3446-0.4256-0.42330.34590.22470.14230.00060.2185-0.01990.09914.592768.086939.8746
30.6931-0.25250.57710.8065-0.27791.0083-0.0024-0.0631-0.02180.00610.0150.01980.0247-0.022-0.01270.01070.00030.01130.0092-0.00060.014514.438857.091432.5284
41.3857-0.09640.10981.44770.16621.26740.03280.2403-0.0044-0.2147-0.01960.0072-0.00340.0327-0.01320.04260.0074-0.00660.0437-0.00020.003812.993760.714111.3648
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A134 - 209
2X-RAY DIFFRACTION2A210 - 220
3X-RAY DIFFRACTION3A221 - 317
4X-RAY DIFFRACTION4A318 - 481

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