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- PDB-9ft6: Crystal structure of human DYRK1A in complex with ARN25697 -

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Basic information

Entry
Database: PDB / ID: 9ft6
TitleCrystal structure of human DYRK1A in complex with ARN25697
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / kinase inhibitors / multitarget compounds / drug discovery / central nervous system / tauopathies
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 / RNA polymerase II CTD heptapeptide repeat kinase activity / protein serine/threonine/tyrosine 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 / : / 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
: / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsDalle Vedove, A. / Demuro, S. / Di Martino, R.M.C. / Balboni, B. / Tripathi, S.K. / Storici, P. / Girotto, S. / Cavalli, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM1311991 United States
CitationJournal: To Be Published
Title: Unveiling the pharmacophoric traits of balanced triple GSK-3B/FYN/DYRK1A inhibitors: rational design and synthesis of novel amino-pyrazole containing scaffolds for the treatment of Alzheimer's ...Title: Unveiling the pharmacophoric traits of balanced triple GSK-3B/FYN/DYRK1A inhibitors: rational design and synthesis of novel amino-pyrazole containing scaffolds for the treatment of Alzheimer's disease and related tauopathies.
Authors: Demuro, S.
History
DepositionJun 24, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release

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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)42,3792
Polymers42,0171
Non-polymers3611
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16740 Å2
Unit cell
Length a, b, c (Å)93.810, 93.810, 48.980
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number77
Space group name H-MP42

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Components

#1: Protein Dual specificity tyrosine-phosphorylation-regulated kinase 1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / MNBH / hMNB


Mass: 42017.426 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: Trichoplusia ni (cabbage looper)
References: UniProt: Q13627, [RNA-polymerase]-subunit kinase, dual-specificity kinase
#2: Chemical ChemComp-A1IE8 / ~{N}4-(3-cyclobutyl-1~{H}-pyrazol-5-yl)-~{N}2-(pyridin-3-ylmethyl)furo[3,2-d]pyrimidine-2,4-diamine


Mass: 361.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N7O / Feature type: SUBJECT OF INVESTIGATION
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: 2.56 Å3/Da / Density % sol: 52.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.4 / Details: 15-20% PEG1000, 50 mM Mes 6.4, 100 mM KCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.907→66.334 Å / Num. obs: 9598 / % possible obs: 100 % / Redundancy: 12.3 % / CC1/2: 0.997 / Rpim(I) all: 0.045 / Net I/σ(I): 13.7
Reflection shellResolution: 2.907→2.958 Å / Mean I/σ(I) obs: 2.1 / Num. unique obs: 483 / CC1/2: 0.696 / Rpim(I) all: 0.404

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→66.33 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 26.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2497 415 4.75 %
Rwork0.2075 --
obs0.2095 8746 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→66.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2806 0 27 0 2833
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032903
X-RAY DIFFRACTIONf_angle_d0.4943916
X-RAY DIFFRACTIONf_dihedral_angle_d13.0891099
X-RAY DIFFRACTIONf_chiral_restr0.041412
X-RAY DIFFRACTIONf_plane_restr0.004497
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.430.30451570.25292715X-RAY DIFFRACTION100
3.44-4.330.29391330.20762756X-RAY DIFFRACTION100
4.33-66.330.20641250.19522860X-RAY DIFFRACTION100

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