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- PDB-6s1b: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s1b
TitleCrystal Structure of DYRK1A with small molecule inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / Kinase / catalytic domain / phosphorylated
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 / 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 / cytoplasm / cytosol
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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. ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-KRQ / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.3 Å
AuthorsSorrell, F.J. / Henderson, S.H. / Redondo, C. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Bountra, C. / Edwards, A.M. / Elkins, J.M.
CitationJournal: To be published
Title: Kinase Scaffold Repurposing in the Public Domain
Authors: Sorrell, F.J. / Henderson, S.H. / Elkins, J.M. / Ward, S.
History
DepositionJun 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Jan 24, 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 16, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,9469
Polymers42,0821
Non-polymers8658
Water8,845491
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-58 kcal/mol
Surface area16490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.310, 70.410, 68.700
Angle α, β, γ (deg.)90.000, 118.040, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-650-

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: 42081.535 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: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KRQ / ~{N}-methyl-4-pyrazolo[1,5-b]pyridazin-3-yl-pyrimidin-2-amine


Mass: 226.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H10N6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 491 / 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: 2.74 Å3/Da / Density % sol: 55.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 2.2M ammonium sulfate -- 0.1M citrate pH 5.3 -- 0.2M sodium/potassium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 1.3→30.6 Å / Num. obs: 103325 / % possible obs: 98.9 % / Redundancy: 2.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.035 / Rrim(I) all: 0.061 / Net I/σ(I): 10.1 / Num. measured all: 280034 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.3-1.3320.6991463973060.5490.5730.9091.195
5.81-30.62.80.02334511920.9980.0140.02439.697.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4mq1

4mq1


Resolution: 1.3→25.162 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 19.04
RfactorNum. reflection% reflection
Rfree0.1786 5187 5.02 %
Rwork0.1606 --
obs0.1615 103305 98.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 108.54 Å2 / Biso mean: 21.3736 Å2 / Biso min: 7.45 Å2
Refinement stepCycle: final / Resolution: 1.3→25.162 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2727 0 67 491 3285
Biso mean--29.1 33.22 -
Num. residues----338
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122908
X-RAY DIFFRACTIONf_angle_d1.1453946
X-RAY DIFFRACTIONf_chiral_restr0.089414
X-RAY DIFFRACTIONf_plane_restr0.007526
X-RAY DIFFRACTIONf_dihedral_angle_d18.9081084
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 (%)
1.3-1.31480.31111550.30573157331295
1.3148-1.33020.30041540.3033093324795
1.3302-1.34650.31441770.28593206338395
1.3465-1.36350.26511800.27163177335799
1.3635-1.38150.29181750.26053227340299
1.3815-1.40040.29331820.26223286346899
1.4004-1.42040.24181500.24873240339099
1.4204-1.44160.2561800.24033281346199
1.4416-1.46410.21231750.221933013476100
1.4641-1.48810.24681630.220832813444100
1.4881-1.51380.24531680.208233053473100
1.5138-1.54130.19781800.19473301348199
1.5413-1.57090.20361730.179232313404100
1.5709-1.6030.1891870.166732753462100
1.603-1.63780.18471780.162933153493100
1.6378-1.67590.18181670.163132943461100
1.6759-1.71780.18151610.159933293490100
1.7178-1.76430.16311640.160632943458100
1.7643-1.81620.17921830.154832993482100
1.8162-1.87480.1511610.15413263342499
1.8748-1.94170.18081960.15132503446100
1.9417-2.01950.16011710.146533333504100
2.0195-2.11130.16431900.13893265345599
2.1113-2.22260.14121710.13653293346499
2.2226-2.36170.15531700.13113316348699
2.3617-2.54390.15081700.13893291346199
2.5439-2.79960.15131880.13823307349599
2.7996-3.2040.17241610.15033285344699
3.204-4.03410.14431680.13653307347599
4.0341-25.16660.19211890.15823316350598
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.91430.2764-0.31810.8592-0.36531.45-0.0332-0.0234-0.04470.0470.0183-0.02450.0652-0.0131-0.01260.10170.0040.00160.1041-0.00180.096425.482-56.541243.7406
20.6524-0.14460.35090.4477-0.25490.75270.0208-0.05240.00760.0020.01610.02240.0229-0.0408-0.02410.10030.00350.00810.0868-0.00120.104815.0723-47.912432.9028
31.0191-0.15410.21930.83760.05210.99930.04010.16050.0046-0.1292-0.00240.0345-0.0211-0.004-0.030.10430.0074-0.00580.1060.00650.082912.1657-44.998311.6554
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 135 through 213 )A135 - 213
2X-RAY DIFFRACTION2chain 'A' and (resid 214 through 320 )A214 - 320
3X-RAY DIFFRACTION3chain 'A' and (resid 322 through 481 )A322 - 481

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