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- PDB-4ylk: Crystal structure of DYRK1A in complex with 10-Chloro-substituted... -

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Basic information

Entry
Database: PDB / ID: 4ylk
TitleCrystal structure of DYRK1A in complex with 10-Chloro-substituted 11H-indolo[3,2-c]quinolone-6-carboxylic acid inhibitor 5s
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


negative regulation of heterochromatin formation / peptidyl-serine autophosphorylation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 ...negative regulation of heterochromatin formation / peptidyl-serine autophosphorylation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 / peptidyl-tyrosine autophosphorylation / cytoskeletal protein binding / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / protein serine/threonine/tyrosine kinase activity / tubulin binding / positive regulation of RNA splicing / non-membrane spanning protein tyrosine kinase activity / peptidyl-tyrosine phosphorylation / tau protein binding / circadian rhythm / nervous system development / peptidyl-serine phosphorylation / actin binding / protein autophosphorylation / protein tyrosine kinase activity / transcription coactivator activity / histone H3T45 kinase activity / protein kinase activity / nuclear speck / protein phosphorylation / axon / ribonucleoprotein complex / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / dendrite / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
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-4E2 / IODIDE ION / 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: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / diffrn_source ...citation / diffrn_source / entity_src_gen / pdbx_struct_oper_list / pdbx_validate_close_contact / 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_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 1.5Oct 23, 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)43,95221
Polymers42,0821
Non-polymers1,87120
Water10,034557
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.970, 69.870, 67.860
Angle α, β, γ (deg.)90.00, 117.69, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-602-

HOH

21A-742-

HOH

31A-748-

HOH

41A-760-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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

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Non-polymers , 5 types, 577 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-4E2 / 10-chloro-2-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid


Mass: 422.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H8ClIN2O2
#5: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 557 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.49 Å3/Da / Density % sol: 50.67 %
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→30.28 Å / Num. obs: 78842 / % possible obs: 97.1 % / Redundancy: 4.4 % / Biso Wilson estimate: 10.6 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 10.7
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.386 / Mean I/σ(I) obs: 3.5 / % possible all: 97.3

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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→30.07 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.799 / SU ML: 0.038 / Cross valid method: THROUGHOUT / ESU R: 0.054 / ESU R Free: 0.056 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17671 3942 5 %RANDOM
Rwork0.15485 ---
obs0.15597 74899 96.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.023 Å2
Baniso -1Baniso -2Baniso -3
1--0.27 Å2-0 Å2-0.51 Å2
2--0.24 Å20 Å2
3---0.36 Å2
Refine analyzeLuzzati coordinate error obs: 0.147 Å
Refinement stepCycle: 1 / Resolution: 1.4→30.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2786 0 101 557 3444
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193082
X-RAY DIFFRACTIONr_bond_other_d0.0010.022950
X-RAY DIFFRACTIONr_angle_refined_deg1.7752.0044164
X-RAY DIFFRACTIONr_angle_other_deg0.77536796
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0685374
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.99124145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.45415549
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.431519
X-RAY DIFFRACTIONr_chiral_restr0.10.2433
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213411
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02727
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_it0.5450.4661403
X-RAY DIFFRACTIONr_mcbond_other0.5440.4641402
X-RAY DIFFRACTIONr_mcangle_it0.9230.6951760
X-RAY DIFFRACTIONr_mcangle_other0.9220.6961761
X-RAY DIFFRACTIONr_scbond_it0.9160.631678
X-RAY DIFFRACTIONr_scbond_other0.9150.6311679
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.3980.8822389
X-RAY DIFFRACTIONr_long_range_B_refined5.7126.8294280
X-RAY DIFFRACTIONr_long_range_B_other5.7116.8294281
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.211 300 -
Rwork0.211 5486 -
obs--97.06 %
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)
11.69680.6429-0.67121.3903-0.61272.2204-0.0239-0.0795-0.17310.0672-0.0044-0.10020.19750.11860.02820.03660.0082-0.00110.0281-0.00150.023725.927447.945843.3183
29.84983.31374.22552.44291.09064.4199-0.289-1.12030.64180.406-0.10490.3309-0.4709-0.47410.39390.2390.10680.00770.2126-0.02550.151614.593868.1739.8452
30.8104-0.22880.64910.775-0.32211.03030.0041-0.0754-0.02770.0050.0180.02750.022-0.0251-0.02210.02970.00070.02250.017-0.00070.020314.433157.158832.5263
41.4686-0.14530.14971.41150.15191.31770.02710.2376-0.0096-0.2137-0.01670.024-0.00070.0355-0.01030.05530.0099-0.00130.04620.00240.002613.0160.759811.3203
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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