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- PDB-7fhs: Crystal structure of DYRK1A in complex with RD0392 -

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Basic information

Entry
Database: PDB / ID: 7fhs
TitleCrystal structure of DYRK1A in complex with RD0392
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / DYRK1A / Kinase / Inhibitor
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-4VZ / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsKikuchi, M. / Sumida, T. / Hosoya, T. / Kii, I. / Umehara, T.
Funding support Japan, 8items
OrganizationGrant numberCountry
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H02856 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)18H04568 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)17H05678 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)16H05926 Japan
Kobayashi Foundation Japan
Life Science Foundation of JAPAN Japan
Tokyo Biochemical Research Foundation Japan
Mochida Memorial Foundation for Medical and Pharmaceutical Research Japan
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A.
Authors: Miyazaki, Y. / Kikuchi, M. / Umezawa, K. / Descamps, A. / Nakamura, D. / Furuie, G. / Sumida, T. / Saito, K. / Kimura, N. / Niwa, T. / Sumida, Y. / Umehara, T. / Hosoya, T. / Kii, I.
History
DepositionJul 30, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: 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
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)169,61513
Polymers168,0304
Non-polymers1,5869
Water4,540252
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5655
Polymers42,0071
Non-polymers5584
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)42,3813
Polymers42,0071
Non-polymers3732
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)42,2892
Polymers42,0071
Non-polymers2811
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)42,3813
Polymers42,0071
Non-polymers3732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.630, 88.182, 228.038
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / MNBH / hMNB


Mass: 42007.391 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Production host: Escherichia coli (E. coli) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-4VZ / (5~{Z})-5-[(3-ethoxy-4-oxidanyl-phenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one


Mass: 281.351 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H11NO3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 252 / 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: 2.62 Å3/Da / Density % sol: 53.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM Bis-Tris propane (pH 8.0), 200 mM Sodium fluoride and 18 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.42→48.12 Å / Num. obs: 67838 / % possible obs: 99.5 % / Redundancy: 6.7 % / Rsym value: 0.15 / Net I/σ(I): 10.2
Reflection shellResolution: 2.42→2.48 Å / Num. unique obs: 4466 / Rsym value: 1.432

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Processing

Software
NameVersionClassification
XDSdata reduction
MOLREPphasing
Aimlessdata scaling
REFMAC5.8.0258refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ANR

3anr


Resolution: 2.42→45 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.912 / SU B: 12.91 / SU ML: 0.274 / Cross valid method: THROUGHOUT / ESU R: 0.455 / ESU R Free: 0.287 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.27494 3319 4.9 %RANDOM
Rwork0.23206 ---
obs0.23414 64462 99.26 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.568 Å2
Baniso -1Baniso -2Baniso -3
1--1.66 Å20 Å20 Å2
2--3.82 Å2-0 Å2
3----2.15 Å2
Refinement stepCycle: 1 / Resolution: 2.42→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11174 0 102 252 11528
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.01211559
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8231.64215594
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.56551364
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.32122.338616
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.371152083
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9761570
X-RAY DIFFRACTIONr_chiral_restr0.0690.21420
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028776
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.5335.2285474
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.747.8326832
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4055.336085
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.98669.67417675
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.42→2.483 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.404 248 -
Rwork0.355 4675 -
obs--98.68 %

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