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- PDB-6s14: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s14
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 / amyloid-beta formation / 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 / amyloid-beta formation / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome / 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 / peptidyl-tyrosine phosphorylation / circadian rhythm / 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 / protein phosphorylation / axon / 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. ...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-KQW / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / 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
Revision 1.3Nov 20, 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

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Assembly

Deposited unit
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9248
Polymers42,0821
Non-polymers8437
Water9,782543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area970 Å2
ΔGint-66 kcal/mol
Surface area16510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.470, 70.300, 68.530
Angle α, β, γ (deg.)90.000, 118.040, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-639-

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.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KQW / ~{N}-cyclopropyl-~{N}-methyl-4-pyrazolo[1,5-b]pyridazin-3-yl-pyrimidin-2-amine


Mass: 266.301 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H14N6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 543 / 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: 2.72 Å3/Da / Density % sol: 54.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 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: 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: 1.05→30.39 Å / Num. obs: 149683 / % possible obs: 75.9 % / Redundancy: 2.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.021 / Rrim(I) all: 0.041 / Net I/σ(I): 15.4 / Num. measured all: 435184
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
1.05-1.081.10.606121811050.3230.5420.8161.27.6
4.7-30.393.50.026784322640.9980.0150.0347.598.9

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Processing

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

4mq1


Resolution: 1.05→24.203 Å / SU ML: 0.06 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.42
RfactorNum. reflection% reflection
Rfree0.1625 7591 5.07 %
Rwork0.1505 --
obs0.1511 149678 75.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 97.37 Å2 / Biso mean: 18.453 Å2 / Biso min: 6.76 Å2
Refinement stepCycle: final / Resolution: 1.05→24.203 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2744 0 64 543 3351
Biso mean--28.03 30.24 -
Num. residues----340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0132893
X-RAY DIFFRACTIONf_angle_d1.2223922
X-RAY DIFFRACTIONf_chiral_restr0.091413
X-RAY DIFFRACTIONf_plane_restr0.009519
X-RAY DIFFRACTIONf_dihedral_angle_d18.8241082
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 (%)
1.05-1.0620.2799110.30792122233
1.062-1.07450.3763370.28162566210
1.0745-1.08760.2991740.28371034110817
1.0876-1.10130.2197860.26271425151123
1.1013-1.11580.2149870.26341876196330
1.1158-1.13110.25671290.23732302243137
1.1311-1.14730.22791630.22972787295045
1.1473-1.16440.22541850.22513284346953
1.1644-1.18260.23782140.20643722393660
1.1826-1.2020.21712560.1974339459571
1.202-1.22270.18912650.195127539282
1.2227-1.24490.19152860.17685470575687
1.2449-1.26890.18512720.17695602587489
1.2689-1.29480.18243140.16495698601292
1.2948-1.32290.18643190.16065803612293
1.3229-1.35370.18063190.16025901622095
1.3537-1.38750.16313170.15816136645398
1.3875-1.42510.16573410.15576099644098
1.4251-1.4670.153090.1516157646698
1.467-1.51430.16743760.15036094647099
1.5143-1.56840.15373070.1426178648599
1.5684-1.63120.14313150.13596219653499
1.6312-1.70540.15473120.1366186649899
1.7054-1.79530.15213200.14066214653499
1.7953-1.90780.14133430.14096220656399
1.9078-2.0550.14483220.13876247656999
2.055-2.26170.13883120.13146252656499
2.2617-2.58860.14373330.137762646597100
2.5886-3.26010.15483450.150362546599100
3.2601-24.2090.17993220.15296360668299
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)
10.87180.0818-0.0531.0449-0.27091.2877-0.0091-0.0525-0.00020.0517-0.0004-0.042-0.0022-0.0074-0.00250.0763-0.00110.0010.0808-0.00610.067324.5892-54.42743.575
20.78520.0690.36810.9883-0.10780.76350.0057-0.0307-0.0329-0.00490.018-0.01520.0442-0.0194-0.01660.07350.00420.00440.062300.073512.8598-47.860929.2156
31.0633-0.21730.2610.77680.07410.92510.04640.16960.0005-0.1345-0.01590.02-0.01880.0235-0.01450.09950.0088-0.00680.0960.00380.069612.3821-45.038311.3458
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 135 through 238 )A135 - 238
2X-RAY DIFFRACTION2chain 'A' and (resid 239 through 320 )A239 - 320
3X-RAY DIFFRACTION3chain 'A' and (resid 322 through 481 )A322 - 481

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