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- PDB-7akb: Structure of DYRK1A in complex with compound 56 -

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Basic information

Entry
Database: PDB / ID: 7akb
TitleStructure of DYRK1A in complex with compound 56
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / PHOSPHOPROTEIN / KINASE SELECTIVITY / SBDD / SMALL MOLECULE 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 / protein serine/threonine/tyrosine kinase activity / cytoskeletal protein binding / 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-RJZ / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsDokurno, P. / Surgenor, A.E. / Kotschy, A.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.
Authors: Weber, C. / Sipos, M. / Paczal, A. / Balint, B. / Kun, V. / Foloppe, N. / Dokurno, P. / Massey, A.J. / Walmsley, D.L. / Hubbard, R.E. / Murray, J. / Benwell, K. / Edmonds, T. / Demarles, D. ...Authors: Weber, C. / Sipos, M. / Paczal, A. / Balint, B. / Kun, V. / Foloppe, N. / Dokurno, P. / Massey, A.J. / Walmsley, D.L. / Hubbard, R.E. / Murray, J. / Benwell, K. / Edmonds, T. / Demarles, D. / Bruno, A. / Burbridge, M. / Cruzalegui, F. / Kotschy, A.
History
DepositionSep 30, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 26, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 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

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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)84,1754
Polymers83,2942
Non-polymers8812
Water1,49583
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0872
Polymers41,6471
Non-polymers4401
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)42,0872
Polymers41,6471
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.480, 83.820, 83.730
Angle α, β, γ (deg.)90.000, 107.810, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: 0 / Auth seq-ID: 142 - 481 / Label seq-ID: 16 - 355

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: 41647.129 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Cell line (production host): pLysS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-RJZ / 4-[3-[2-(6-bromanylpyridin-2-yl)oxyethyl]-2-methyl-imidazo[4,5-b]pyridin-5-yl]pyridine-2,6-diamine


Mass: 440.297 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18BrN7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.31 Å3/Da / Density % sol: 46.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 7% PEG 8k, 0.15M Ca acetate, 16% ethylene glycol, 0.1M MES buffer pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 30, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.76→57.8 Å / Num. obs: 19086 / % possible obs: 98.1 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.109 / Net I/σ(I): 4.9
Reflection shellResolution: 2.76→2.84 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.453 / Mean I/σ(I) obs: 2 / Num. unique obs: 1387 / % possible all: 97.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vx3

2vx3


Resolution: 2.8→25 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.884 / SU B: 18.419 / SU ML: 0.347 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.402 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2478 954 5.2 %RANDOM
Rwork0.1938 ---
obs0.1966 17393 97.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 149.41 Å2 / Biso mean: 48.273 Å2 / Biso min: 16.35 Å2
Baniso -1Baniso -2Baniso -3
1-4.14 Å20 Å2-0.18 Å2
2---3.61 Å20 Å2
3----0.34 Å2
Refinement stepCycle: final / Resolution: 2.8→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5400 0 56 83 5539
Biso mean--50.15 32.72 -
Num. residues----668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0135605
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175228
X-RAY DIFFRACTIONr_angle_refined_deg1.4731.6447579
X-RAY DIFFRACTIONr_angle_other_deg1.2161.57512099
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7835666
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.02721.655290
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.22415985
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.1571538
X-RAY DIFFRACTIONr_chiral_restr0.0620.2694
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026151
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021215
Refine LS restraints NCS

Ens-ID: 1 / Number: 10173 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.17 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.8→2.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.346 124 -
Rwork0.273 2480 -
all-2604 -
obs--97.06 %

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