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- PDB-6s17: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s17
TitleCrystal Structure of DYRK1A with small molecule inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / Kinase / catalytic domain / phosphorylated
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 / cytosol / cytoplasm
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-KQK / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.1 Å
AuthorsSorrell, F.J. / Henderson, S.H. / Redondo, C. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Bountra, C. / Edwards, A.M. / Elkins, J.M.
CitationJournal: To be published
Title: Kinase Scaffold Repurposing in the Public Domain
Authors: Sorrell, F.J. / Henderson, S.H. / Elkins, J.M. / Ward, S.
History
DepositionJun 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Jan 24, 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 / refine
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine.pdbx_diffrn_id
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)43,04412
Polymers42,0821
Non-polymers96311
Water8,089449
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-14 kcal/mol
Surface area16570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.870, 70.550, 68.330
Angle α, β, γ (deg.)90.000, 117.820, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-620-

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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-KQK / ~{N},~{N}-dimethyl-4-pyrazolo[1,5-b]pyridazin-3-yl-pyrimidin-2-amine


Mass: 240.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H12N6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 449 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.69 Å3/Da / Density % sol: 54.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.6M ammonium sulfate -- 0.1M citrate pH 5.3 -- 0.2M sodium/potassium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 1.1→30.46 Å / Num. obs: 137242 / % possible obs: 80.2 % / Redundancy: 4 % / Biso Wilson estimate: 12.26 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.027 / Rrim(I) all: 0.06 / Net I/σ(I): 11.7 / Num. measured all: 554971
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.1-1.1320.621614730300.5520.470.7851.324.3
4.92-30.464.50.037882419580.9980.0190.04232.998.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4mq1

4mq1


Resolution: 1.1→25.065 Å / SU ML: 0.09 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1625 6929 5.05 %
Rwork0.1491 130301 -
obs0.1498 137230 80.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 116.52 Å2 / Biso mean: 21.7222 Å2 / Biso min: 8.34 Å2
Refinement stepCycle: final / Resolution: 1.1→25.065 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2753 0 115 449 3317
Biso mean--29.14 33.66 -
Num. residues----343
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.1-1.11250.2812660.29081133119921
1.1125-1.12560.3102580.27811403146126
1.1256-1.13940.3319980.26451666176431
1.1394-1.15380.25711140.25691884199835
1.1538-1.1690.26091280.24682266239442
1.169-1.1850.23611310.22622700283149
1.185-1.20190.23251710.21983089326058
1.2019-1.21980.23422150.21723847406272
1.2198-1.23890.21632790.2064360463981
1.2389-1.25920.22812280.20154547477583
1.2592-1.28090.21732410.18614625486686
1.2809-1.30420.19682610.18164746500788
1.3042-1.32930.19572700.17234791506189
1.3293-1.35640.18512580.17074844510290
1.3564-1.38590.17363120.16825117542995
1.3859-1.41820.17642780.16485167544595
1.4182-1.45360.18322540.16265189544396
1.4536-1.49290.16512510.15775175542696
1.4929-1.53680.17022930.15195242553596
1.5368-1.58640.17062600.14525221548197
1.5864-1.64310.16032540.14085230548496
1.6431-1.70890.1692950.1435263555897
1.7089-1.78670.15662240.14525277550197
1.7867-1.88080.16082880.13885239552797
1.8808-1.99860.14183000.13645323562398
1.9986-2.15290.14152790.13285313559298
2.1529-2.36940.13982540.12455386564098
2.3694-2.71190.14142950.1325357565299
2.7119-3.41530.14672740.14235425569999
3.4153-25.07170.16433000.15175476577699
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)
11.73730.1238-0.88180.8768-0.22282.6277-0.0661-0.1096-0.15670.05540.0085-0.04710.18220.04880.04350.1064-0.00870.00530.08270.01850.096524.7392-60.973446.144
25.2778-3.518-1.14186.0411.37153.0952-0.0814-0.01970.12330.05090.06210.143-0.2622-0.12620.00820.08520.00020.00740.07150.01080.069127.0777-44.330637.7829
32.4363-0.16211.26320.415-0.41372.0861-0.0032-0.19040.02160.04410.05790.0082-0.0585-0.1267-0.06430.1095-0.00640.01620.08630.00740.090418.1099-51.079440.6193
47.1293-3.5845-0.72093.3255-1.45222.4653-0.00440.0216-0.1619-0.2759-0.02150.11310.4683-0.1641-0.01820.189-0.0353-0.02110.08080.01340.13814.243-62.231823.7514
52.61070.19270.42421.2062-0.26351.03560.0015-0.0958-0.06220.02610.01210.0567-0.0179-0.0618-0.01450.09350.01050.01060.0796-0.00050.082812.834-44.866729.9276
65.5344-2.7011.70122.42120.37191.83730.18850.35080.6987-0.56870.1069-0.7861-0.32690.3515-0.45070.17390.00330.07460.15310.04880.245131.9773-42.259320.875
71.57740.10640.31810.63040.25271.32470.03450.1769-0.0269-0.1074-0.0035-0.0464-0.02460.1102-0.02650.11510.01880.00260.11250.00060.103418.228-46.819512.6461
83.37481.79590.04913.961-1.03285.98330.06380.64410.3313-0.87720.0767-0.0577-0.24190.1368-0.07630.31630.03960.06430.39850.05540.153225.1032-43.1103-2.885
93.85261.8047-4.05366.4345-2.55696.4118-0.08510.9676-0.6346-0.55980.0852-0.17460.46360.18440.00710.2760.0761-0.01320.3214-0.07180.164518.0715-53.594-1.6393
102.1743-0.409-0.4890.56850.15592.08370.12110.2216-0.1328-0.1348-0.00230.15620.182-0.206-0.11440.16930.0003-0.07070.2019-0.01370.16880.0741-51.48748.5483
114.26191.2482-0.65473.1983-0.29622.6086-0.0849-0.23710.0297-0.10290.01350.3929-0.0877-0.45210.02950.1050.0348-0.02750.20210.00540.1654-3.3862-44.566415.7712
121.8939-1.074-0.78892.02270.99983.2265-0.00150.04610.201-0.07180.04070.01-0.16480.063-0.03890.11230.0156-0.00840.07270.01010.10512.2094-34.872416.5191
133.75-1.9101-0.31365.73021.34240.454-0.1152-0.22270.22340.28930.14840.5258-0.1838-0.32070.07190.15050.07420.03280.17540.02680.1647-0.9902-35.307123.7001
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 134:192)A134 - 192
2X-RAY DIFFRACTION2(chain A and resid 193:215)A193 - 215
3X-RAY DIFFRACTION3(chain A and resid 216:248)A216 - 248
4X-RAY DIFFRACTION4(chain A and resid 249:256)A249 - 256
5X-RAY DIFFRACTION5(chain A and resid 257:313)A257 - 313
6X-RAY DIFFRACTION6(chain A and resid 314:321)A314 - 321
7X-RAY DIFFRACTION7(chain A and resid 322:389)A322 - 389
8X-RAY DIFFRACTION8(chain A and resid 390:404)A390 - 404
9X-RAY DIFFRACTION9(chain A and resid 405:416)A405 - 416
10X-RAY DIFFRACTION10(chain A and resid 417:439)A417 - 439
11X-RAY DIFFRACTION11(chain A and resid 440:457)A440 - 457
12X-RAY DIFFRACTION12(chain A and resid 458:474)A458 - 474
13X-RAY DIFFRACTION13(chain A and resid 475:482)A475 - 482

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