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- PDB-7ajv: Structure of DYRK1A in complex with compound 38 -

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Basic information

Entry
Database: PDB / ID: 7ajv
TitleStructure of DYRK1A in complex with compound 38
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / PHOSPHOPROTEIN / KINASE SELECTIVITY / SBDD / SMALL MOLECULE INHIBITOR
Function / homology
Function and homology information


negative regulation of heterochromatin formation / peptidyl-serine autophosphorylation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 ...negative regulation of heterochromatin formation / peptidyl-serine autophosphorylation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 / peptidyl-tyrosine autophosphorylation / cytoskeletal protein binding / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / protein serine/threonine/tyrosine kinase activity / tubulin binding / positive regulation of RNA splicing / non-membrane spanning protein tyrosine kinase activity / peptidyl-tyrosine phosphorylation / tau protein binding / circadian rhythm / nervous system development / peptidyl-serine phosphorylation / actin binding / protein autophosphorylation / protein tyrosine kinase activity / transcription coactivator activity / histone H3T45 kinase activity / protein kinase activity / nuclear speck / protein phosphorylation / axon / ribonucleoprotein complex / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / dendrite / 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
Chem-RKK / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 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
Revision 1.3Oct 9, 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
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,0426
Polymers83,2942
Non-polymers7484
Water5,441302
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0213
Polymers41,6471
Non-polymers3742
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)42,0213
Polymers41,6471
Non-polymers3742
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.079, 84.758, 84.685
Angle α, β, γ (deg.)90.000, 107.540, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 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-RKK / 4-(2,3-dibutylimidazo[4,5-b]pyridin-5-yl)pyridine-2,6-diamine / 4-{2,3-dibutyl-3H-imidazo[4,5-b]pyridin-5-yl}pyridine-2,6-diamine


Mass: 338.450 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H26N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / 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: 2.39 Å3/Da / Density % sol: 48.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 12% PEG3350, 0.2M ammonium sulphate, 0.05M Mg sulphate, 0.05M Na citrate buffer pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→55.4 Å / Num. obs: 45971 / % possible obs: 96.3 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 13.1
Reflection shellResolution: 2.07→2.14 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.715 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 4570 / % possible all: 98

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Phasing

PhasingMethod: molecular replacement

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Processing

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

2vx3


Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.945 / SU B: 5.665 / SU ML: 0.141 / SU R Cruickshank DPI: 0.2172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.217 / ESU R Free: 0.177 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2193 2197 5 %RANDOM
Rwork0.1805 ---
obs0.1824 41760 95.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 102.66 Å2 / Biso mean: 32.945 Å2 / Biso min: 17.76 Å2
Baniso -1Baniso -2Baniso -3
1-0.93 Å20 Å2-1.56 Å2
2---0.93 Å2-0 Å2
3---0.83 Å2
Refinement stepCycle: final / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5409 0 52 302 5763
Biso mean--29.21 35.16 -
Num. residues----668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0135590
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175268
X-RAY DIFFRACTIONr_angle_refined_deg1.5231.6437547
X-RAY DIFFRACTIONr_angle_other_deg1.3051.57512198
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4645664
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.70221.736288
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.35715999
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.241537
X-RAY DIFFRACTIONr_chiral_restr0.0750.2693
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026118
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021203
LS refinement shellResolution: 2.1→2.212 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.286 333 -
Rwork0.255 6080 -
all-6413 -
obs--97.26 %

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