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- PDB-6eiq: DYRK1A in complex with XMD14-124 -

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Basic information

Entry
Database: PDB / ID: 6eiq
TitleDYRK1A in complex with XMD14-124
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
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 / 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
Chem-B6Z / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRothweiler, U.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors.
Authors: Czarna, A. / Wang, J. / Zelencova, D. / Liu, Y. / Deng, X. / Choi, H.G. / Zhang, T. / Zhou, W. / Chang, J.W. / Kildalsen, H. / Seternes, O.M. / Gray, N.S. / Engh, R.A. / Rothweiler, U.
History
DepositionSep 19, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 17, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)172,3108
Polymers170,6164
Non-polymers1,6944
Water4,396244
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0782
Polymers42,6541
Non-polymers4241
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)43,0782
Polymers42,6541
Non-polymers4241
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)43,0782
Polymers42,6541
Non-polymers4241
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)43,0782
Polymers42,6541
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.560, 87.600, 229.040
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 / hMNB


Mass: 42653.992 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-B6Z / [4-azanyl-2-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1,3-thiazol-5-yl]-phenyl-methanone


Mass: 423.531 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H25N5O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 244 / 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: 2.57 Å3/Da / Density % sol: 52.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M KSCN; 0.1M NaCl; 12% PEG 3350, pH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.984003 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.984003 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.751
11K, H, -L20.249
ReflectionResolution: 2.3→50 Å / Num. obs: 77090 / % possible obs: 97.1 % / Redundancy: 3.8 % / Net I/σ(I): 9.45
Reflection shellResolution: 2.3→2.44 Å / Mean I/σ(I) obs: 0.99 / Num. unique all: 12348 / Num. unique obs: 48049 / CC1/2: 0.419 / Rrim(I) all: 1.206 / % possible all: 97.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4nct

4nct


Resolution: 2.3→48.1 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.925 / SU B: 10.829 / SU ML: 0.146 / Cross valid method: THROUGHOUT / ESU R: 0.069 / ESU R Free: 0.05 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25245 3846 5 %RANDOM
Rwork0.21812 ---
obs0.21986 73223 96.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 55.491 Å2
Baniso -1Baniso -2Baniso -3
1-11.33 Å20 Å20 Å2
2--25.45 Å20 Å2
3----36.79 Å2
Refinement stepCycle: 1 / Resolution: 2.3→48.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10948 0 120 244 11312
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01911341
X-RAY DIFFRACTIONr_bond_other_d0.0030.0210832
X-RAY DIFFRACTIONr_angle_refined_deg1.2971.98215333
X-RAY DIFFRACTIONr_angle_other_deg0.9813.00424866
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.10951338
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.52123.989534
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.988151984
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4331565
X-RAY DIFFRACTIONr_chiral_restr0.0670.21625
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02112706
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022707
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_it0.8964.1145382
X-RAY DIFFRACTIONr_mcbond_other0.8964.1145381
X-RAY DIFFRACTIONr_mcangle_it1.5586.1646710
X-RAY DIFFRACTIONr_mcangle_other1.5586.1646711
X-RAY DIFFRACTIONr_scbond_it0.684.1455959
X-RAY DIFFRACTIONr_scbond_other0.684.1455960
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.1646.2088624
X-RAY DIFFRACTIONr_long_range_B_refined2.98547.4312691
X-RAY DIFFRACTIONr_long_range_B_other2.96347.4112681
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.296→2.356 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 279 -
Rwork0.284 5183 -
obs--94.42 %
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)
10.5571-0.387-0.1410.35080.23870.29680.04750.0359-0.0586-0.0046-0.03930.04350.0191-0.0209-0.00820.0339-0.00060.00120.16170.00590.20480.8162-16.7861-8.0271
20.3038-0.0838-0.44790.23580.39551.1232-0.00030.13690.01340.0490.10890.01180.07650.0653-0.10860.02280.0274-0.03140.3026-0.05640.17063.2368-20.8781-48.8563
30.37390.0028-0.14760.19920.24781.39490.07460.17380.00730.0267-0.1205-0.08590.08260.01390.04590.03380.0601-0.02590.2680.03090.23440.463-9.1441-37.6865
40.21780.044-0.25770.14370.00981.3060.09790.04630.09070.0541-0.04130.0303-0.13280.0351-0.05660.06080.01110.00940.15520.03810.217315.89817.5395-19.4941
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A134 - 480
2X-RAY DIFFRACTION2B133 - 480
3X-RAY DIFFRACTION3C135 - 479
4X-RAY DIFFRACTION4D134 - 479

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