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- PDB-8t2h: DYRK1A complex with DYR530 -

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Basic information

Entry
Database: PDB / ID: 8t2h
TitleDYRK1A complex with DYR530
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsLIGASE/LIGASE INHIBITOR / Kinase / Inhibitor / Alzheimer's Disease / LIGASE / LIGASE-LIGASE INHIBITOR complex
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
: / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsMontfort, W.R. / Basantes, L.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG067926 United States
CitationJournal: To Be Published
Title: Discovery of DYR684, a Potent, Selective, Metabolically Stable, DYRK1A/B PROTAC utilizing a Novel Cereblon Molecular Glue
Authors: Montfort, W.R. / Basantes, L.E.
History
DepositionJun 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)86,1838
Polymers84,8782
Non-polymers1,3056
Water6,377354
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2355
Polymers42,4391
Non-polymers7964
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)42,9483
Polymers42,4391
Non-polymers5102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.472, 83.213, 146.675
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: 42438.785 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 (E. coli)
References: UniProt: Q13627, [RNA-polymerase]-subunit kinase, dual-specificity kinase
#2: Chemical ChemComp-XIR / (4P)-4-{(3M)-3-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyridin-2-amine


Mass: 417.482 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C23H24FN7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 354 / 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: 2.27 Å3/Da / Density % sol: 45.86 % / Description: Rod
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 1.8 M sodium malonate, 1.3% PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: LIQUID ANODE / Type: BRUKER METALJET / Wavelength: 1.34 Å
DetectorType: Bruker PHOTON III / Detector: PIXEL / Date: May 23, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.34 Å / Relative weight: 1
ReflectionResolution: 1.85→24.88 Å / Num. obs: 67138 / % possible obs: 100 % / Redundancy: 7 % / CC1/2: 0.996 / Rmerge(I) obs: 0.119 / Net I/σ(I): 10.7
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 2 / Num. unique obs: 18823 / CC1/2: 0.48 / Χ2: 0.96 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0411refinement
PROTEUM2data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→24.88 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.938 / SU B: 7.706 / SU ML: 0.098 / Cross valid method: THROUGHOUT / ESU R: 0.249 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21303 3381 5 %RANDOM
Rwork0.16329 ---
obs0.16584 63675 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.451 Å2
Baniso -1Baniso -2Baniso -3
1--0.28 Å20 Å2-0 Å2
2--0.11 Å2-0 Å2
3---0.17 Å2
Refinement stepCycle: 1 / Resolution: 1.85→24.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5581 0 93 354 6028
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0125838
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165593
X-RAY DIFFRACTIONr_angle_refined_deg1.4981.6537879
X-RAY DIFFRACTIONr_angle_other_deg0.4991.57912874
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8715683
X-RAY DIFFRACTIONr_dihedral_angle_2_deg17.02540
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.441101048
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0780.2829
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026716
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021382
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_it1.4392.0842735
X-RAY DIFFRACTIONr_mcbond_other1.4392.0842735
X-RAY DIFFRACTIONr_mcangle_it2.2173.7243417
X-RAY DIFFRACTIONr_mcangle_other2.2173.7253418
X-RAY DIFFRACTIONr_scbond_it1.5482.3793103
X-RAY DIFFRACTIONr_scbond_other1.5482.3793104
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.2864.2214463
X-RAY DIFFRACTIONr_long_range_B_refined3.85323.47256
X-RAY DIFFRACTIONr_long_range_B_other3.7522.847183
X-RAY DIFFRACTIONr_rigid_bond_restr3.099311431
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 219 -
Rwork0.29 4678 -
obs--99.98 %

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