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- PDB-7ajs: Structure of DYRK1A in complex with compound 33 -

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Basic information

Entry
Database: PDB / ID: 7ajs
TitleStructure of DYRK1A in complex with compound 33
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / PHOSPHOPROTEIN / KINASE SELECTIVITY / SBDD / SMALL MOLECULE INHIBITOR
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 / 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-RKH / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.15 Å
AuthorsDokurno, P. / Surgenor, A.E. / Kotschy, A.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.
Authors: Weber, C. / Sipos, M. / Paczal, A. / Balint, B. / Kun, V. / Foloppe, N. / Dokurno, P. / Massey, A.J. / Walmsley, D.L. / Hubbard, R.E. / Murray, J. / Benwell, K. / Edmonds, T. / Demarles, D. ...Authors: Weber, C. / Sipos, M. / Paczal, A. / Balint, B. / Kun, V. / Foloppe, N. / Dokurno, P. / Massey, A.J. / Walmsley, D.L. / Hubbard, R.E. / Murray, J. / Benwell, K. / Edmonds, T. / Demarles, D. / Bruno, A. / Burbridge, M. / Cruzalegui, F. / Kotschy, A.
History
DepositionSep 29, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 26, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 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

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


Theoretical massNumber of molelcules
Total (without water)82,8786
Polymers82,2292
Non-polymers6494
Water10,809600
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,4463
Polymers41,1151
Non-polymers3312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,4323
Polymers41,1151
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.775, 85.598, 153.165
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 41114.547 Da / Num. of mol.: 2
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-RKH / 4-(2-methyl-1-benzofuran-5-yl)pyridine-2,6-diamine


Mass: 239.273 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H13N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 600 / 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: 2.34 Å3/Da / Density % sol: 47.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 12% PEG3350, 0.1M MES buffer pH6.5, 0.2M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Apr 22, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 39803 / % possible obs: 87.3 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.111 / Net I/σ(I): 10.1
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.633 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 0 / % possible all: 83

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Phasing

PhasingMethod: molecular replacement

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Processing

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

2vx3


Resolution: 2.15→25 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.506 / SU ML: 0.112 / SU R Cruickshank DPI: 0.2766 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.277 / ESU R Free: 0.19 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1999 1789 4.8 %RANDOM
Rwork0.1609 ---
obs0.1628 35504 86.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 91.42 Å2 / Biso mean: 27.523 Å2 / Biso min: 9.03 Å2
Baniso -1Baniso -2Baniso -3
1-2.47 Å20 Å2-0 Å2
2---1.44 Å20 Å2
3----1.03 Å2
Refinement stepCycle: final / Resolution: 2.15→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5442 0 46 600 6088
Biso mean--30.66 37.08 -
Num. residues----670
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0135645
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175313
X-RAY DIFFRACTIONr_angle_refined_deg1.6231.6427628
X-RAY DIFFRACTIONr_angle_other_deg1.3241.57712312
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2685674
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.70121.818297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.235151014
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.211538
X-RAY DIFFRACTIONr_chiral_restr0.0830.2699
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026195
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021219
LS refinement shellResolution: 2.15→2.265 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.254 274 -
Rwork0.226 5279 -
all-5553 -
obs--90.44 %

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