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- PDB-6s1h: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s1h
TitleCrystal Structure of DYRK1A with small molecule inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
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 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 / 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 / tau protein binding / non-membrane spanning protein tyrosine kinase activity / 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-KQZ / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.05 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)42,7958
Polymers42,0821
Non-polymers7147
Water9,620534
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-26 kcal/mol
Surface area15730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.630, 69.680, 67.690
Angle α, β, γ (deg.)90.000, 117.800, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-633-

HOH

21A-1069-

HOH

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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.: 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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KQZ / ~{N},~{N}-dimethyl-4-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine


Mass: 239.276 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13N5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 534 / Source method: isolated from a natural source / Formula: H2O
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: 2.62 Å3/Da / Density % sol: 53.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.8M 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: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.05→30.11 Å / Num. obs: 174657 / % possible obs: 91.9 % / Redundancy: 3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.033 / Rrim(I) all: 0.061 / Net I/σ(I): 11.1 / Num. measured all: 523518
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
1.05-1.081.70.6341096165480.5090.5880.868147
4.7-30.113.20.047700121830.9950.030.05628.498.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4mq1

4mq1


Resolution: 1.05→30.113 Å / SU ML: 0.09 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 15.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1545 8962 5.13 %
Rwork0.1404 165690 -
obs0.1411 174652 91.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 85.13 Å2 / Biso mean: 19.5206 Å2 / Biso min: 7.86 Å2
Refinement stepCycle: final / Resolution: 1.05→30.113 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2740 0 76 534 3350
Biso mean--23.28 30.54 -
Num. residues----340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063093
X-RAY DIFFRACTIONf_angle_d1.0314208
X-RAY DIFFRACTIONf_chiral_restr0.129434
X-RAY DIFFRACTIONf_plane_restr0.007569
X-RAY DIFFRACTIONf_dihedral_angle_d19.1131181
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 (%)
1.05-1.06190.43731220.40512521264342
1.0619-1.07440.34491610.33812973313450
1.0744-1.08750.31552240.29043394361857
1.0875-1.10130.28772210.25513927414866
1.1013-1.11580.22362410.22734453469475
1.1158-1.13110.21542800.19625018529883
1.1311-1.14720.18923350.17695498583392
1.1472-1.16440.17953380.16295806614498
1.1644-1.18260.1723280.15745907623599
1.1826-1.2020.15943720.151659306302100
1.202-1.22270.16093330.143959546287100
1.2227-1.24490.15962910.137560476338100
1.2449-1.26890.16383230.135559856308100
1.2689-1.29480.15313110.13159826293100
1.2948-1.32290.14913170.129559876304100
1.3229-1.35370.13623290.126860326361100
1.3537-1.38750.14783040.128159496253100
1.3875-1.42510.1433170.12560186335100
1.4251-1.4670.13273200.124359886308100
1.467-1.51430.1483600.121659646324100
1.5143-1.56850.12743090.120960336342100
1.5685-1.63120.13833140.11860296343100
1.6312-1.70550.13043000.123160186318100
1.7055-1.79540.15353070.131560226329100
1.7954-1.90790.14683370.128559756312100
1.9079-2.05510.13873060.131660476353100
2.0551-2.26190.14872940.124160416335100
2.2619-2.5890.14233240.132760106334100
2.589-3.26130.15223280.14960496377100
3.2613-30.12580.16433160.15136133644999

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