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- PDB-7o7k: Crystal structure of the human DYRK1A kinase domain bound to abem... -

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Basic information

Entry
Database: PDB / ID: 7o7k
TitleCrystal structure of the human DYRK1A kinase domain bound to abemaciclib
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / serine/threonine kinase / CMGC kinase / dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / transcription / abemaciclib
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-6ZV / CITRATE ANION / : / DI(HYDROXYETHYL)ETHER / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsKaltheuner, I.H. / Anand, K. / Geyer, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)GE 976/9-2 Germany
CitationJournal: Nat Commun / Year: 2021
Title: Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation.
Authors: Kaltheuner, I.H. / Anand, K. / Moecking, J. / Duster, R. / Wang, J. / Gray, N.S. / Geyer, M.
History
DepositionApr 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 1, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)87,29431
Polymers84,1632
Non-polymers3,13129
Water6,756375
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,57614
Polymers42,0821
Non-polymers1,49413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,71817
Polymers42,0821
Non-polymers1,63716
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.705, 109.985, 112.497
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 134 through 159 or resid 161...
21(chain B and (resid 134 through 159 or resid 161...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 134 through 159 or resid 161...A134 - 159
121(chain A and (resid 134 through 159 or resid 161...A161 - 204
131(chain A and (resid 134 through 159 or resid 161...A206 - 225
141(chain A and (resid 134 through 159 or resid 161...A227 - 409
151(chain A and (resid 134 through 159 or resid 161...A413 - 480
161(chain A and (resid 134 through 159 or resid 161...A801 - 914
211(chain B and (resid 134 through 159 or resid 161...B134 - 159
221(chain B and (resid 134 through 159 or resid 161...B161 - 204
231(chain B and (resid 134 through 159 or resid 161...B206 - 225
241(chain B and (resid 134 through 159 or resid 161...B227 - 480
251(chain B and (resid 134 through 159 or resid 161...B801 - 908

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / hMNB


Mass: 42081.535 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q13627, dual-specificity kinase

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Non-polymers , 6 types, 404 molecules

#2: Chemical
ChemComp-FLC / CITRATE ANION / Citric acid


Mass: 189.100 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H5O7
#3: Chemical ChemComp-6ZV / N-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl}-5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]py rimidin-2-amine / Abemaciclib / Abemaciclib


Mass: 506.593 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32F2N8 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-LI / LITHIUM ION / Lithium


Mass: 6.941 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Li
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 375 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.82 Å3/Da / Density % sol: 56.37 %
Crystal growTemperature: 288 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 14-16% PEG 4000, 0.1 M sodium citrate (pH 6.5) and 0.1 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.82→44.69 Å / Num. obs: 85615 / % possible obs: 99.59 % / Redundancy: 13.4 % / CC1/2: 0.999 / Rrim(I) all: 0.07891 / Net I/σ(I): 16.36
Reflection shellResolution: 1.82→1.885 Å / Num. unique obs: 8460 / CC1/2: 0.836 / Rrim(I) all: 1.718 / % possible all: 99.35

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vx3

2vx3


Resolution: 1.82→41.93 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 22.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2049 4283 5 %
Rwork0.1774 81327 -
obs0.1788 85610 99.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 107.36 Å2 / Biso mean: 47.5774 Å2 / Biso min: 26.52 Å2
Refinement stepCycle: final / Resolution: 1.82→41.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5663 0 224 375 6262
Biso mean--47.87 51.49 -
Num. residues----690
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A3365X-RAY DIFFRACTION11.377TORSIONAL
12B3365X-RAY DIFFRACTION11.377TORSIONAL
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 (%)
1.82-1.840.33681360.30422582271896
1.84-1.860.28921410.29192679282099
1.86-1.880.32441410.281526842825100
1.88-1.910.2991400.25792658279899
1.91-1.930.29131410.236626772818100
1.93-1.960.27251420.22182679282199
1.96-1.990.25731400.216126692809100
1.99-2.020.23981420.2082681282399
2.02-2.050.251410.203226752816100
2.05-2.080.22391420.189726972839100
2.08-2.120.25931420.184326892831100
2.12-2.160.23821430.174427172860100
2.16-2.20.20521410.175727052846100
2.2-2.240.20941410.171726952836100
2.24-2.290.26841430.173826952838100
2.29-2.340.18551430.177127052848100
2.34-2.40.23491420.179527032845100
2.4-2.470.20711420.184427012843100
2.47-2.540.2171420.189126892831100
2.54-2.620.24741440.193627392883100
2.62-2.720.2211410.19012683282499
2.72-2.830.23381430.203827162859100
2.83-2.950.20731430.206227272870100
2.95-3.110.23261440.191727252869100
3.11-3.30.20421450.182827552900100
3.3-3.560.21251440.177327362880100
3.56-3.920.15411460.159127732919100
3.92-4.480.17561480.142127932941100
4.48-5.650.17541450.15582764290999
5.65-44.690.19871550.177329363091100
Refinement TLS params.Method: refined / Origin x: 23.0427 Å / Origin y: 7.0928 Å / Origin z: 16.7133 Å
111213212223313233
T0.2253 Å2-0.0157 Å2-0.0208 Å2-0.3172 Å20.001 Å2--0.2437 Å2
L0.6187 °2-0.5429 °2-0.2303 °2-1.9269 °20.3784 °2--0.5566 °2
S0.0236 Å °0.0536 Å °-0.0087 Å °-0.0175 Å °-0.0229 Å °0.07 Å °0.0506 Å °-0.0135 Å °-0.0048 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA134 - 480
2X-RAY DIFFRACTION1allA801 - 915
3X-RAY DIFFRACTION1allB133 - 480
4X-RAY DIFFRACTION1allB801 - 912
5X-RAY DIFFRACTION1allD1 - 858
6X-RAY DIFFRACTION1allC1 - 2

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