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- PDB-4yu2: Crystal structure of DYRK1A with harmine-derivatized AnnH-75 inhibitor -

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Basic information

Entry
Database: PDB / ID: 4yu2
TitleCrystal structure of DYRK1A with harmine-derivatized AnnH-75 inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / DYRK1A / down syndrome / inhibitor / harmine / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4H5 / 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. / Wurzlbauer, A. / Nowak, R. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bracher, F. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Molecules / Year: 2020
Title: How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition-The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine.
Authors: Wurzlbauer, A. / Ruben, K. / Gurdal, E. / Chaikuad, A. / Knapp, S. / Sippl, W. / Becker, W. / Bracher, F.
History
DepositionMar 18, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 10, 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)170,38015
Polymers168,3264
Non-polymers2,05411
Water5,513306
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5473
Polymers42,0821
Non-polymers4662
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)42,8366
Polymers42,0821
Non-polymers7545
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)42,6444
Polymers42,0821
Non-polymers5623
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)42,3532
Polymers42,0821
Non-polymers2721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)265.567, 65.444, 138.648
Angle α, β, γ (deg.)90.00, 114.44, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-612-

HOH

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 / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSAA134 - 48010 - 356
21LYSLYSBB134 - 48010 - 356
12VALVALAA135 - 48011 - 356
22VALVALCC135 - 48011 - 356
13VALVALAA135 - 48011 - 356
23VALVALDD135 - 48011 - 356
14VALVALBB135 - 48011 - 356
24VALVALCC135 - 48011 - 356
15VALVALBB135 - 48011 - 356
25VALVALDD135 - 48011 - 356
16VALVALCC135 - 48111 - 357
26VALVALDD135 - 48111 - 357

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 / Fragment: UNP residues 127-485
Source method: isolated from a genetically manipulated source
Details: kinase domain 127-485 / Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Plasmid: pNIC28-Bsa4 / Details (production host): 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.: 3 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical
ChemComp-4H5 / (1-chloro-7-methoxy-9H-beta-carbolin-9-yl)acetonitrile


Mass: 271.702 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H10ClN3O
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 306 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.26 Å3/Da / Density % sol: 62.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 31% PEG 400, 0.2 M lithium sulfate, 0.1 M Tris, pH 9.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 31, 2013
RadiationMonochromator: Si (111) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.9→48.34 Å / Num. obs: 48349 / % possible obs: 99.5 % / Redundancy: 6.7 % / Biso Wilson estimate: 58.2 Å2 / Rmerge(I) obs: 0.126 / Net I/σ(I): 10.6
Reflection shellResolution: 2.9→3.06 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.928 / Mean I/σ(I) obs: 2 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WO6

2wo6


Resolution: 2.9→48.34 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.901 / SU B: 47.572 / SU ML: 0.44 / Cross valid method: THROUGHOUT / ESU R Free: 0.415 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27715 2443 5.1 %RANDOM
Rwork0.24302 ---
obs0.24478 45905 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 75.108 Å2
Baniso -1Baniso -2Baniso -3
1-0.28 Å2-0 Å2-2.92 Å2
2---2.02 Å20 Å2
3---3.12 Å2
Refine analyzeLuzzati coordinate error obs: 0.515 Å
Refinement stepCycle: 1 / Resolution: 2.9→48.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11253 0 135 306 11694
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01911735
X-RAY DIFFRACTIONr_bond_other_d0.0050.0211117
X-RAY DIFFRACTIONr_angle_refined_deg1.2231.98615871
X-RAY DIFFRACTIONr_angle_other_deg0.825325541
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.70851399
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.76823.768552
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.426152039
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9911576
X-RAY DIFFRACTIONr_chiral_restr0.0630.21672
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02113121
X-RAY DIFFRACTIONr_gen_planes_other0.0050.022795
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_it1.9843.1815576
X-RAY DIFFRACTIONr_mcbond_other1.9843.1825577
X-RAY DIFFRACTIONr_mcangle_it3.4014.7666961
X-RAY DIFFRACTIONr_mcangle_other3.44.7676962
X-RAY DIFFRACTIONr_scbond_it2.4533.3766159
X-RAY DIFFRACTIONr_scbond_other2.3993.3586143
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.6584.998881
X-RAY DIFFRACTIONr_long_range_B_refined7.57527.31413723
X-RAY DIFFRACTIONr_long_range_B_other7.57427.31913724
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A221010.05
12B221010.05
21A221870.05
22C221870.05
31A221150.05
32D221150.05
41B220410.04
42C220410.04
51B220440.04
52D220440.04
61C219880.05
62D219880.05
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.419 197 -
Rwork0.393 3358 -
obs--99.38 %
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)
14.01320.57421.76671.49910.21611.50920.2455-0.2724-0.2672-0.0262-0.15310.15150.1983-0.3516-0.09240.2929-0.12140.14880.59540.03840.1735-41.2569-43.64722.0025
25.6909-1.10050.86015.40570.74063.50940.1308-0.1591-0.48070.14480.03-0.6068-0.00590.2581-0.16070.4511-0.13770.10280.4722-0.08640.187711.8262-16.469131.8933
32.75110.69481.32841.65350.85393.4960.1997-0.1965-0.01920.3123-0.18930.06360.0004-0.2649-0.01050.2055-0.04290.08930.22030.00090.0491-5.9335-27.770715.4181
41.7315-0.3068-1.00661.79160.71373.4025-0.0444-0.2230.117-0.27950.06920.1021-0.4671-0.2056-0.02480.5846-0.03890.10810.5946-0.08630.0578-4.8271-56.922656.5865
51.40990.03550.11561.72470.69563.8811-0.08910.14750.19110.0969-0.01030.1987-0.75530.04980.09940.4664-0.08310.04780.62110.21940.2339-66.381-51.422133.1828
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B134 - 481
2X-RAY DIFFRACTION2A134 - 219
3X-RAY DIFFRACTION3A220 - 482
4X-RAY DIFFRACTION4C135 - 481
5X-RAY DIFFRACTION5D135 - 481

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