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- PDB-7a5d: Structure of DYRK1A in complex with compound 16 -

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Basic information

Entry
Database: PDB / ID: 7a5d
TitleStructure of DYRK1A in complex with compound 16
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / PHOSPHOPROTEIN / KINASE / SBDD / FBLD / SMALL MOLECULE INHIBITOR
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 / actin binding / protein autophosphorylation / 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 / cytoplasm / cytosol
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / 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
Similarity search - Domain/homology
Chem-QYW / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsDokurno, P. / Surgenor, A.E. / Hubbard, R.E.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B.
Authors: Lee Walmsley, D. / Murray, J.B. / Dokurno, P. / Massey, A.J. / Benwell, K. / Fiumana, A. / Foloppe, N. / Ray, S. / Smith, J. / Surgenor, A.E. / Edmonds, T. / Demarles, D. / Burbridge, M. / ...Authors: Lee Walmsley, D. / Murray, J.B. / Dokurno, P. / Massey, A.J. / Benwell, K. / Fiumana, A. / Foloppe, N. / Ray, S. / Smith, J. / Surgenor, A.E. / Edmonds, T. / Demarles, D. / Burbridge, M. / Cruzalegui, F. / Kotschy, A. / Hubbard, R.E.
History
DepositionAug 21, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 21, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)41,9684
Polymers41,6471
Non-polymers3213
Water5,477304
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-18 kcal/mol
Surface area15410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.696, 81.696, 123.601
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-718-

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: 41647.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Cell line (production host): pLysS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-QYW / 4-azanyl-2-methyl-6-pyridin-3-yl-7~{H}-pyrrolo[2,3-d]pyrimidine-5-carbonitrile


Mass: 250.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10N6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 304 / 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: 2.48 Å3/Da / Density % sol: 50.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 0.1M MES buffer at pH 6.5, 12% Peg3350, 0.2M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 14, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.78→28.9 Å / Num. obs: 40618 / % possible obs: 99.6 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.067 / Net I/σ(I): 16.6
Reflection shellResolution: 1.78→1.83 Å / Redundancy: 4 % / Rmerge(I) obs: 0.603 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 0 / % possible all: 95.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0258refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vx3

2vx3


Resolution: 1.8→25 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.675 / SU ML: 0.079 / SU R Cruickshank DPI: 0.106 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.106 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1978 1982 5 %RANDOM
Rwork0.1673 ---
obs0.1689 37483 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 108.65 Å2 / Biso mean: 30.602 Å2 / Biso min: 15.18 Å2
Baniso -1Baniso -2Baniso -3
1-1 Å20 Å2-0 Å2
2--1 Å2-0 Å2
3----2 Å2
Refinement stepCycle: final / Resolution: 1.8→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2695 0 21 304 3020
Biso mean--25.49 42.14 -
Num. residues----331
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132785
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172635
X-RAY DIFFRACTIONr_angle_refined_deg1.6911.6443758
X-RAY DIFFRACTIONr_angle_other_deg1.4421.5776112
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8565331
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.58122145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.98115513
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8851518
X-RAY DIFFRACTIONr_chiral_restr0.0920.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023045
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02594
LS refinement shellResolution: 1.8→1.897 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.286 289 -
Rwork0.266 5370 -
all-5659 -
obs--99.89 %

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