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- PDB-6s1j: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s1j
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


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 DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome ...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 DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome / amyloid-beta formation / G0 and Early G1 / peptidyl-tyrosine autophosphorylation / cytoskeletal protein binding / protein serine/threonine/tyrosine kinase activity / 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 / 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. ...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-KRK / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.408 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

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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)43,20113
Polymers42,0821
Non-polymers1,11912
Water5,621312
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-23 kcal/mol
Surface area15890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.202, 69.671, 67.440
Angle α, β, γ (deg.)90.000, 117.540, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-610-

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
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

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Non-polymers , 5 types, 324 molecules

#2: Chemical ChemComp-KRK / 3-[2-[(3~{S})-3-fluoranylpyrrolidin-1-yl]pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine


Mass: 284.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13FN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 312 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.6 Å3/Da / Density % sol: 52.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 2.2M ammonium sulfate -- 0.1M citrate pH 5.7 -- 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: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jan 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.41→59.8 Å / Num. obs: 75809 / % possible obs: 96.4 % / Redundancy: 12.2 % / Biso Wilson estimate: 12.44 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.195 / Rpim(I) all: 0.058 / Rrim(I) all: 0.204 / Net I/σ(I): 9.5 / Num. measured all: 924128 / Scaling rejects: 508
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
1.41-1.488.82.6817634686760.40.9292.8471.876
4.45-59.812.20.1183138825690.9940.0340.12320.9100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.3data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4mq1

4mq1


Resolution: 1.408→59.801 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1758 3728 4.93 %
Rwork0.1554 71824 -
obs0.1564 75552 96.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 90.8 Å2 / Biso mean: 21.035 Å2 / Biso min: 6.52 Å2
Refinement stepCycle: final / Resolution: 1.408→59.801 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2734 0 124 312 3170
Biso mean--34.43 30.31 -
Num. residues----341
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4081-1.42590.2726940.25371783187765
1.4259-1.44470.24161090.23971920202970
1.4447-1.46450.26581040.22652152225678
1.4645-1.48540.22861430.21512304244784
1.4854-1.50760.24041380.21492632277096
1.5076-1.53110.22411390.201527472886100
1.5311-1.55620.21011400.191727872927100
1.5562-1.58310.2041380.183427602898100
1.5831-1.61190.20341290.18327622891100
1.6119-1.64290.22871330.177327762909100
1.6429-1.67640.20161330.179127762909100
1.6764-1.71290.21361550.180227302885100
1.7129-1.75270.19411430.179327632906100
1.7527-1.79650.18631540.181427692923100
1.7965-1.84510.19871330.165527862919100
1.8451-1.89940.18481310.156327862917100
1.8994-1.96070.18131320.15227582890100
1.9607-2.03080.15441420.138327732915100
2.0308-2.11210.14891600.129327682928100
2.1121-2.20830.15091500.128827482898100
2.2083-2.32470.16081380.129227992937100
2.3247-2.47030.13851450.136127632908100
2.4703-2.66110.16261510.140627842935100
2.6611-2.92890.161350.144827782913100
2.9289-3.35260.15491400.14728082948100
3.3526-4.22380.1511750.13327642939100
4.2238-59.85490.2041440.169528482992100
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)
11.74980.216-0.63831.4359-0.40562.4628-0.0669-0.0913-0.15230.06620.0179-0.06970.2010.06790.00360.0999-0.00090.00250.06810.01070.080424.8606-60.67145.4997
25.0905-4.113-1.00027.21831.3723.3262-0.1684-0.04890.08780.06270.14330.1471-0.268-0.03980.02540.0876-0.00470.00280.08770.0120.074927.0551-44.186437.0225
32.0313-0.04890.89190.4378-0.26941.7897-0.016-0.18790.02020.02940.06850.0427-0.0475-0.0941-0.08880.10430.00160.01050.07270.00280.08518.0802-50.913240.1889
45.9843-1.7878-1.83961.05480.17031.38310.0578-0.051-0.2494-0.2181-0.02240.2230.4848-0.2018-0.04210.2069-0.0387-0.0490.09090.01560.15863.7424-61.746423.0694
52.75080.44950.44951.7474-0.04391.00660.0027-0.082-0.0090.05370.01750.1233-0.0084-0.0823-0.01960.1090.00940.0060.08910.00510.079110.8528-44.315628.8702
63.6543.1483-0.05724.0582-0.70442.32070.1316-0.07310.18730.0646-0.0240.2739-0.083-0.0503-0.10830.10350.01010.01290.08660.00750.106411.6641-48.101133.7742
71.9937-2.0255-1.83492.0591.83552.17170.06960.06060.2667-0.19950.0385-0.2669-0.12910.1508-0.09640.12970.0033-0.00050.1740.02470.19428.9598-41.102125.4734
81.99310.0660.20780.80090.11771.52350.04830.1871-0.0664-0.1265-0.0121-0.02540.05170.0937-0.03160.1120.0228-0.00490.1002-0.00040.078817.0991-47.754813.253
91.81831.07060.18953.62190.15334.87210.0970.64450.2357-0.5951-0.0852-0.0267-0.27950.37280.00950.26880.03580.03460.36420.0570.170824.6736-41.985-1.038
102.59590.3673-2.29650.18960.04913.04830.07130.6404-0.1051-0.1538-0.08250.1199-0.0593-0.30540.01820.22840.0287-0.07470.2769-0.03640.15597.2489-50.77293.074
113.69342.20080.32314.53420.20712.97180.3837-0.057-0.6468-0.26940.08520.59890.4516-0.6736-0.35010.2225-0.0332-0.12790.32560.00760.3363-5.7325-53.541513.4606
124.43561.45020.90173.99270.64770.9739-0.0349-0.25860.1174-0.0817-0.08050.4473-0.0906-0.32610.08990.12340.0331-0.03580.188-0.00690.1563-1.8975-43.127315.1357
132.5176-1.4026-1.34442.16361.3213.9188-0.00560.00240.2348-0.09080.037-0.0292-0.18060.1341-0.01160.12090.0137-0.02160.08440.01240.102112.3092-34.950316.6298
144.7382-5.0843-0.99975.78610.82060.4032-0.2026-0.1617-0.0760.16510.08770.4876-0.1482-0.25960.13270.11030.03490.00340.12570.01420.129-0.7011-36.121921.9336
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 134:193)A134 - 193
2X-RAY DIFFRACTION2(chain A and resid 194:214)A194 - 214
3X-RAY DIFFRACTION3(chain A and resid 215:248)A215 - 248
4X-RAY DIFFRACTION4(chain A and resid 249:256)A249 - 256
5X-RAY DIFFRACTION5(chain A and resid 257:299)A257 - 299
6X-RAY DIFFRACTION6(chain A and resid 300:308)A300 - 308
7X-RAY DIFFRACTION7(chain A and resid 309:320)A309 - 320
8X-RAY DIFFRACTION8(chain A and resid 322:382)A322 - 382
9X-RAY DIFFRACTION9(chain A and resid 383:407)A383 - 407
10X-RAY DIFFRACTION10(chain A and resid 414:426)A414 - 426
11X-RAY DIFFRACTION11(chain A and resid 427:441)A427 - 441
12X-RAY DIFFRACTION12(chain A and resid 442:458)A442 - 458
13X-RAY DIFFRACTION13(chain A and resid 459:474)A459 - 474
14X-RAY DIFFRACTION14(chain A and resid 475:481)A475 - 481

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