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- PDB-6ej4: DYRK1A in complex with XMD7-112 -

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Basic information

Entry
Database: PDB / ID: 6ej4
TitleDYRK1A in complex with XMD7-112
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Function / homology
Function and homology information


regulation of amyloid-beta formation / negative regulation of heterochromatin formation / regulation of neurofibrillary tangle assembly / histone H3T45 kinase activity / dual-specificity kinase / splicing factor binding / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / regulation of alternative mRNA splicing, via spliceosome / negative regulation of microtubule polymerization ...regulation of amyloid-beta formation / negative regulation of heterochromatin formation / regulation of neurofibrillary tangle assembly / histone H3T45 kinase activity / dual-specificity kinase / splicing factor binding / [RNA-polymerase]-subunit kinase / tau-protein kinase activity / regulation of alternative mRNA splicing, via spliceosome / negative regulation of microtubule polymerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome / G0 and Early G1 / cytoskeletal protein binding / protein serine/threonine/tyrosine kinase activity / RNA polymerase II CTD heptapeptide repeat kinase activity / tubulin binding / peptidyl-tyrosine phosphorylation / positive regulation of RNA splicing / non-membrane spanning protein tyrosine kinase activity / circadian rhythm / tau protein binding / nervous system development / protein autophosphorylation / actin binding / protein tyrosine kinase activity / transcription coactivator activity / protein phosphorylation / protein kinase activity / nuclear speck / ribonucleoprotein complex / axon / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / centrosome / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
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. ...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-B7W / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 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 20, 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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
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)171,7618
Polymers170,6164
Non-polymers1,1454
Water1,00956
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9402
Polymers42,6541
Non-polymers2861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9402
Polymers42,6541
Non-polymers2861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9402
Polymers42,6541
Non-polymers2861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9402
Polymers42,6541
Non-polymers2861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.150, 88.190, 229.200
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 / 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-B7W / 3-(3-pyridin-3-yl-1~{H}-pyrrolo[2,3-b]pyridin-5-yl)aniline


Mass: 286.331 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H14N4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.61 Å3/Da / Density % sol: 52.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M KSCN; 0.05M NaCl; 16% PEG 3350, pH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976251 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976251 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.737
11K, H, -L20.263
ReflectionResolution: 2.88→50 Å / Num. obs: 40869 / % possible obs: 98.8 % / Redundancy: 5 % / CC1/2: 0.993 / Rrim(I) all: 0.166 / Net I/σ(I): 9.85
Reflection shellResolution: 2.88→3.05 Å / Mean I/σ(I) obs: 1.96 / Num. unique obs: 6282 / CC1/2: 0.793 / Rrim(I) all: 0.691 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4nct

4nct


Resolution: 2.88→48.3 Å / Cor.coef. Fo:Fc: 0.902 / Cor.coef. Fo:Fc free: 0.86 / SU B: 36.553 / SU ML: 0.352 / Cross valid method: THROUGHOUT / ESU R Free: 0.09 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27019 2020 4.9 %RANDOM
Rwork0.21999 ---
obs0.22246 38847 98.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 57.455 Å2
Baniso -1Baniso -2Baniso -3
1-7.14 Å2-0 Å2-0 Å2
2--49.13 Å20 Å2
3----56.27 Å2
Refinement stepCycle: 1 / Resolution: 2.88→48.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10878 0 88 56 11022
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01911232
X-RAY DIFFRACTIONr_bond_other_d0.0010.0210351
X-RAY DIFFRACTIONr_angle_refined_deg1.271.97915190
X-RAY DIFFRACTIONr_angle_other_deg0.9393.00223954
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.57151333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.46123.989529
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.549151950
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8211565
X-RAY DIFFRACTIONr_chiral_restr0.0730.21622
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02112357
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022376
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_it0.6713.5115368
X-RAY DIFFRACTIONr_mcbond_other0.6713.5115367
X-RAY DIFFRACTIONr_mcangle_it1.2175.2596689
X-RAY DIFFRACTIONr_mcangle_other1.2175.2596690
X-RAY DIFFRACTIONr_scbond_it0.3833.5245864
X-RAY DIFFRACTIONr_scbond_other0.3833.5245865
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.7295.2948502
X-RAY DIFFRACTIONr_long_range_B_refined2.62140.44512645
X-RAY DIFFRACTIONr_long_range_B_other2.62140.44412646
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.879→2.954 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.395 138 -
Rwork0.296 2578 -
obs--89.46 %
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)
10.44960.39230.10890.35520.11960.41630.05320.00750.0806-0.00890.00660.05350.0590.0099-0.05980.31070.01310.00390.0019-0.01880.4720.779416.867.9473
20.36190.13680.2590.33640.61411.52710.0043-0.15550.0389-0.09960.16730.022-0.09730.239-0.17160.2196-0.04320.02540.3205-0.06170.2933.154720.968348.8462
30.5880.03350.32370.29550.33591.07960.1787-0.233-0.0236-0.099-0.1438-0.111-0.072-0.1853-0.03490.209-0.08680.04320.19290.0380.366240.72679.20137.5209
40.50320.02940.44630.0740.04382.01830.1786-0.1169-0.1109-0.1215-0.0339-0.01660.156-0.0355-0.14470.31270.0041-0.03320.04040.04510.408416.1836-17.372219.6257
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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