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- PDB-6t6a: Crystal structure of DYRK1A complexed with KuFal319 (compound 11) -

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Basic information

Entry
Database: PDB / ID: 6t6a
TitleCrystal structure of DYRK1A complexed with KuFal319 (compound 11)
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / DYRK1A / splicing kinase / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
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 mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator ...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 mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 / tau protein binding / non-membrane spanning protein tyrosine kinase activity / 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 / 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. ...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
4-chloranyl-5~{H}-cyclohepta[b]indol-10-one / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsChaikuad, A. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Kunick, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Molecules / Year: 2019
Title: [ b ]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors.
Authors: Lechner, C. / Flasshoff, M. / Falke, H. / Preu, L. / Loaec, N. / Meijer, L. / Knapp, S. / Chaikuad, A. / Kunick, C.
History
DepositionOct 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: Database references / Category: citation / Item: _citation.title
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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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


Theoretical massNumber of molelcules
Total (without water)171,23525
Polymers168,3264
Non-polymers2,90921
Water5,513306
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1828
Polymers42,0821
Non-polymers1,1017
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)42,8907
Polymers42,0821
Non-polymers8086
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8907
Polymers42,0821
Non-polymers8086
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,2743
Polymers42,0821
Non-polymers1922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)244.882, 65.395, 148.055
Angle α, β, γ (deg.)90.000, 115.180, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: VAL / Beg label comp-ID: VAL / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: 0 / Auth seq-ID: 135 - 481 / Label seq-ID: 11 - 357

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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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: 42081.535 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2 / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-MLW / 4-chloranyl-5~{H}-cyclohepta[b]indol-10-one


Mass: 229.662 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C13H8ClNO / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 306 / 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: 3.19 Å3/Da / Density % sol: 61.4 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 31% PEG 400, 0.2 M lithium sulfate and 0.1 M tris, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Oct 31, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.8→133.982 Å / Num. all: 51386 / Num. obs: 51386 / % possible obs: 97.6 % / Redundancy: 3.6 % / Rpim(I) all: 0.072 / Rrim(I) all: 0.143 / Rsym value: 0.122 / Net I/av σ(I): 5.3 / Net I/σ(I): 7.5 / Num. measured all: 182486
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.8-2.953.70.5351.42747275230.3160.6250.5352.198.5
2.95-3.133.40.36622333169400.2240.4310.3662.996.2
3.13-3.353.40.243.12246265350.1460.2830.244.496.3
3.35-3.613.80.1564.62396162880.0890.180.1567.199
3.61-3.963.70.1215.82118457620.070.140.121999
3.96-4.433.50.09771829751890.0570.1130.0971198.1
4.43-5.113.20.0818.31446344880.0510.0960.08111.895.6
5.11-6.263.80.0788.81489839250.0450.0910.07811.498.6
6.26-8.853.30.0649.21007730110.0380.0750.06412.597
8.85-46.2283.70.0579.4634117250.0330.0660.05717.596.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
SCALA3.3.21data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YLL

4yll


Resolution: 2.8→133.98 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.903 / WRfactor Rfree: 0.2302 / WRfactor Rwork: 0.1921 / FOM work R set: 0.7989 / SU B: 30.029 / SU ML: 0.292 / SU R Cruickshank DPI: 1.6749 / SU Rfree: 0.3428 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.675 / ESU R Free: 0.343 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.242 2622 5.1 %RANDOM
Rwork0.2054 ---
obs0.2073 48750 97.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 138.36 Å2 / Biso mean: 48.579 Å2 / Biso min: 3.85 Å2
Baniso -1Baniso -2Baniso -3
1-1.76 Å2-0 Å2-2.17 Å2
2--1.17 Å2-0 Å2
3----0.62 Å2
Refinement stepCycle: final / Resolution: 2.8→133.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11328 0 178 306 11812
Biso mean--61.01 28.73 -
Num. residues----1388
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01911771
X-RAY DIFFRACTIONr_bond_other_d0.0050.0211293
X-RAY DIFFRACTIONr_angle_refined_deg1.4331.98515870
X-RAY DIFFRACTIONr_angle_other_deg0.969325986
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.68351386
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.52823.838555
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.832152117
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5671575
X-RAY DIFFRACTIONr_chiral_restr0.0710.21674
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02113034
X-RAY DIFFRACTIONr_gen_planes_other0.0050.022777
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A227530.05
12B227530.05
21A229570.05
22C229570.05
31A229590.04
32D229590.04
41B227000.05
42C227000.05
51B227490.05
52D227490.05
61C230260.02
62D230260.02
LS refinement shellResolution: 2.8→2.873 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 185 -
Rwork0.316 3614 -
all-3799 -
obs--98.34 %
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)
12.43190.14250.02052.16560.04932.4355-0.0784-0.0499-0.15210.01030.1584-0.3190.1020.0316-0.080.1743-0.03310.06530.0412-0.06120.1168.159617.110233.1099
20.5274-0.03810.17780.47140.26890.83840.09330.008-0.00230.0503-0.0328-0.02440.0042-0.1192-0.06050.1523-0.01620.07520.08410.02650.1002-7.46885.513614.6628
34.0404-1.24350.96113.04450.61620.94270.6751-0.1001-0.38470.0169-0.30980.14230.2003-0.1199-0.36530.1583-0.1268-0.05580.36370.07430.2457-54.0808-15.9524-16.6203
42.6139-0.38970.44920.5438-0.01460.3790.37870.1346-0.21950.0185-0.1161-0.03810.1869-0.1499-0.26250.1293-0.1104-0.11760.27770.10050.1801-40.5741-14.3921-8.9401
50.9177-0.2610.21540.90270.43030.61950.2059-0.2205-0.071-0.0222-0.0212-0.09930.0886-0.3252-0.18470.07-0.1018-0.01640.30140.08910.0626-32.8832-6.88729.5088
61.7871-1.4140.52041.71860.3281.20640.116-0.03320.2098-0.08780.0885-0.3222-0.07470.0697-0.20450.2245-0.04820.10870.0678-0.05420.1221.5113-25.157640.6117
70.7647-0.4098-0.20470.6623-0.02920.5347-0.0219-0.1201-0.0146-0.08010.0790.0097-0.02990.0429-0.05720.1819-0.0070.0720.1171-0.01330.0497-17.351-22.377162.8004
80.76260.12110.43061.42020.68340.5730.03460.3222-0.0458-0.0241-0.0282-0.0133-0.06060.2653-0.00640.0808-0.1175-0.03110.51320.10430.0519-55.4711-24.155929.9017
91.02970.34610.01720.59020.09120.8384-0.08630.09520.09410.11910.01850.1582-0.2152-0.08480.06780.1468-0.03410.00440.23530.10710.1015-65.3603-12.343752.6458
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A135 - 219
2X-RAY DIFFRACTION2A220 - 481
3X-RAY DIFFRACTION3B135 - 219
4X-RAY DIFFRACTION4B220 - 322
5X-RAY DIFFRACTION5B323 - 481
6X-RAY DIFFRACTION6C135 - 243
7X-RAY DIFFRACTION7C244 - 481
8X-RAY DIFFRACTION8D135 - 322
9X-RAY DIFFRACTION9D323 - 481

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