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- PDB-6qu2: Crystal structure of DYRK1A complexed with FC162 inhibitor -

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Basic information

Entry
Database: PDB / ID: 6qu2
TitleCrystal structure of DYRK1A complexed with FC162 inhibitor
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 / 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-JHW / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsChaikuad, A. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Besson, T. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: To Be Published
Title: Crystal structure of DYRK1A complexed with FC162 inhibitor
Authors: Chaikuad, A. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Besson, T. / Knapp, S. / Structural Genomics Consortium (SGC)
History
DepositionFeb 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 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)171,99427
Polymers168,3264
Non-polymers3,66823
Water4,342241
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0617
Polymers42,0821
Non-polymers9796
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)43,1199
Polymers42,0821
Non-polymers1,0378
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)43,0276
Polymers42,0821
Non-polymers9455
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)42,7885
Polymers42,0821
Non-polymers7074
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)245.886, 65.889, 148.337
Angle α, β, γ (deg.)90.000, 115.500, 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: LYS / Beg label comp-ID: LYS / End auth comp-ID: THR / End label comp-ID: THR / Refine code: 0 / Auth seq-ID: 134 - 482 / Label seq-ID: 10 - 358

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

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Protein , 1 types, 4 molecules ABCD

#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

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Non-polymers , 6 types, 264 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-JHW / 8-cyclopropyl-2-pyridin-3-yl-[1,3]thiazolo[5,4-f]quinazolin-9-one


Mass: 320.368 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H12N4OS
#6: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 241 / Source method: isolated from a natural source / Formula: H2O

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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: 3.23 Å3/Da / Density % sol: 61.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.75
Details: 31% PEG 400, 0.25 M lithium sulfate and 0.1 M Tris, pH 8.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 18, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.9→49.04 Å / Num. obs: 47406 / % possible obs: 98.8 % / Redundancy: 2.9 % / Biso Wilson estimate: 35.9 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.098 / Rrim(I) all: 0.173 / Net I/σ(I): 6.9
Reflection shellResolution: 2.9→3.06 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.573 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 6853 / CC1/2: 0.661 / Rpim(I) all: 0.448 / Rrim(I) all: 0.794 / % possible all: 99

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4yll

4yll


Resolution: 2.9→49.04 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.889 / SU B: 33.589 / SU ML: 0.3 / SU R Cruickshank DPI: 0.3218 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.368
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2417 2257 4.8 %RANDOM
Rwork0.2018 ---
obs0.2037 45144 98.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 117.76 Å2 / Biso mean: 48.558 Å2 / Biso min: 10.12 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20 Å2-0.55 Å2
2---1.38 Å20 Å2
3---0.37 Å2
Refinement stepCycle: final / Resolution: 2.9→49.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11385 0 248 241 11874
Biso mean--54.17 27.95 -
Num. residues----1396
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01911941
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211154
X-RAY DIFFRACTIONr_angle_refined_deg1.2031.97616110
X-RAY DIFFRACTIONr_angle_other_deg0.786325878
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.25451402
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.27423.703559
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.83152134
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0361580
X-RAY DIFFRACTIONr_chiral_restr0.0680.21704
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02113423
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022485
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A237300.03
12B237300.03
21A235760.05
22C235760.05
31A236260.05
32D236260.05
41B235220.04
42C235220.04
51B236020.04
52D236020.04
61C234260.05
62D234260.05
LS refinement shellResolution: 2.9→2.975 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 182 -
Rwork0.334 3289 -
all-3471 -
obs--98.55 %
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)
10.72860.17630.16620.59460.52861.08270.1485-0.08660.04340.1021-0.04510.03090.0138-0.0314-0.10340.2014-0.06820.10850.2625-0.01390.0751-3.63-25.09319.327
20.8147-0.2724-0.68251.10680.80821.04040.0485-0.08720.0571-0.41550.1347-0.1165-0.30840.1063-0.18320.3286-0.11520.08070.3124-0.03650.0609-11.32-57.05855.642
30.3979-0.11510.10521.05030.42461.4264-0.03390.11980.0207-0.01790.11430.1448-0.1143-0.0491-0.08040.0262-0.01570.00570.43930.15450.0755-60.114-52.57239.948
41.5142-0.11620.80820.3964-0.07550.92030.2184-0.0245-0.2619-0.0432-0.06930.02150.0621-0.0996-0.14910.1249-0.0526-0.01360.3323-0.00550.0705-40.611-44.802-2.476
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A134 - 482
2X-RAY DIFFRACTION2B134 - 482
3X-RAY DIFFRACTION3C134 - 482
4X-RAY DIFFRACTION4D134 - 482

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