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- PDB-6s11: Crystal Structure of DYRK1A with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 6s11
TitleCrystal Structure of DYRK1A with small molecule inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1A
KeywordsTRANSFERASE / Kinase / catalytic domain / phosphorylated
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 / cytosol / 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. ...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-KQE / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.445 Å
AuthorsSorrell, F.J. / Henderson, S.H. / Redondo, C. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Bountra, C. / Edwards, A.M. / Elkins, J.M.
CitationJournal: To be published
Title: Kinase Scaffold Repurposing in the Public Domain
Authors: Sorrell, F.J. / Henderson, S.H. / Elkins, J.M. / Ward, S.
History
DepositionJun 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Jan 24, 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 / refine / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine.pdbx_diffrn_id / _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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)84,9115
Polymers84,1632
Non-polymers7483
Water7,152397
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4733
Polymers42,0821
Non-polymers3922
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)42,4382
Polymers42,0821
Non-polymers3561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)168.615, 168.615, 62.154
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and ((resid 136 through 137 and (name N...
21(chain B and (resid 136 through 178 or (resid 179...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11TYRTYRASNASN(chain A and ((resid 136 through 137 and (name N...AA136 - 13712 - 13
12LYSLYSLYSLYS(chain A and ((resid 136 through 137 and (name N...AA134 - 48010 - 356
13LYSLYSLYSLYS(chain A and ((resid 136 through 137 and (name N...AA134 - 48010 - 356
14LYSLYSLYSLYS(chain A and ((resid 136 through 137 and (name N...AA134 - 48010 - 356
21TYRTYRASPASP(chain B and (resid 136 through 178 or (resid 179...BB136 - 17812 - 54
22ARGARGARGARG(chain B and (resid 136 through 178 or (resid 179...BB17955
23TYRTYRLYSLYS(chain B and (resid 136 through 178 or (resid 179...BB136 - 48012 - 356
24TYRTYRLYSLYS(chain B and (resid 136 through 178 or (resid 179...BB136 - 48012 - 356
25TYRTYRLYSLYS(chain B and (resid 136 through 178 or (resid 179...BB136 - 48012 - 356
26TYRTYRLYSLYS(chain B and (resid 136 through 178 or (resid 179...BB136 - 48012 - 356
27TYRTYRLYSLYS(chain B and (resid 136 through 178 or (resid 179...BB136 - 48012 - 356

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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: 42081.535 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 BL21(DE3) (bacteria) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-KQE / 6-pyridin-4-yl-3-[3-(trifluoromethyloxy)phenyl]imidazo[1,2-b]pyridazine


Mass: 356.301 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H11F3N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 397 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 3.24 Å3/Da / Density % sol: 62.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 20% PEG6000 -- 10% ethylene glycol -- 0.2M ammonium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.44→84.31 Å / Num. obs: 37660 / % possible obs: 100 % / Redundancy: 9.1 % / CC1/2: 0.989 / Rmerge(I) obs: 0.273 / Rpim(I) all: 0.095 / Rrim(I) all: 0.29 / Net I/σ(I): 8.2 / Num. measured all: 343840 / Scaling rejects: 114
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.44-2.547.81.0453304742230.6310.3971.1192.9100
8.82-84.318.60.06574688650.9980.0230.06918.599.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.66 Å84.31 Å
Translation6.66 Å84.31 Å

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
PHASER2.7.17phasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4nct

4nct


Resolution: 2.445→84.308 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2102 1897 5.04 %
Rwork0.1708 35736 -
obs0.1728 37633 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 105.64 Å2 / Biso mean: 36.0879 Å2 / Biso min: 8.87 Å2
Refinement stepCycle: final / Resolution: 2.445→84.308 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5324 0 53 397 5774
Biso mean--28.32 36.38 -
Num. residues----673
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.015543
X-RAY DIFFRACTIONf_angle_d1.0387513
X-RAY DIFFRACTIONf_chiral_restr0.069812
X-RAY DIFFRACTIONf_plane_restr0.0071013
X-RAY DIFFRACTIONf_dihedral_angle_d7.33999
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2919X-RAY DIFFRACTION9.882TORSIONAL
12B2919X-RAY DIFFRACTION9.882TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.445-2.50610.2731370.21925432680
2.5061-2.57390.25461460.20725202666
2.5739-2.64970.24141160.191125392655
2.6497-2.73520.24991170.191225472664
2.7352-2.83290.24121510.189325402691
2.8329-2.94640.19591340.171625332667
2.9464-3.08050.22521310.172525252656
3.0805-3.24290.18281430.169525502693
3.2429-3.44610.21611240.170225602684
3.4461-3.71210.19891260.155825322658
3.7121-4.08570.19741530.146825612714
4.0857-4.67690.18151520.140325452697
4.6769-5.89220.20921270.166325792706
5.8922-84.35760.19421400.187626622802
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)
12.49550.6820.4672.61511.07232.1947-0.0420.115-0.1464-0.13380.401-0.44440.09610.1843-0.17860.22360.01160.00170.2946-0.03990.179379.6172-65.3706-17.9131
21.7008-0.4787-0.12781.0777-0.10261.28230.04430.09170.20830.0615-0.0433-0.0941-0.11090.0934-0.01340.0964-0.01590.01830.1877-0.00370.097774.104-57.8256-11.5096
32.7255-0.446-0.09752.7414-0.33542.92960.034-0.13170.57050.2981-0.0478-0.2472-0.54950.0246-0.01060.1445-0.0758-0.00170.2578-0.04910.153557.4484-51.692-10.6717
40.6685-0.0031-0.01080.2318-0.22251.13740.03530.0275-0.02840.0177-0.03430.0340.05460.08950.00410.1259-0.04260.03090.145-0.01940.132461.9955-57.9504-0.5994
50.5340.24740.23260.8675-0.05950.2854-0.0325-0.0804-0.15640.00170.0653-0.08810.0794-0.0652-0.01570.1295-0.0510.03080.1819-0.01490.100251.2132-71.12956.1238
62.32840.8059-1.59751.3958-0.04692.38380.02040.1161-0.40290.0257-0.0335-0.03090.0023-0.06840.02680.2146-0.0877-0.02030.2073-0.01760.13738.1282-82.55445.0002
70.85160.14520.25490.7863-0.17511.16550.1019-0.14210.03950.2169-0.00030.0067-0.1096-0.0261-0.0320.1439-0.06190.03760.1988-0.02290.102350.5252-63.70117.5104
82.559-0.0141-0.4361.4833-0.64281.44470.0316-0.051-0.5559-0.1648-0.1693-0.28780.07780.31340.09020.211-0.0259-0.06020.349-0.01280.362878.1371-85.175525.9851
90.64510.3479-0.50450.2546-0.31160.39770.0231-0.0668-1.1638-0.40950.10770.24350.6874-0.21180.22350.4663-0.1623-0.25090.35730.1620.987458.5773-102.865333.4208
100.5088-0.3642-0.20521.4692-0.2720.98990.1561-0.7177-0.41980.4576-0.12710.13080.17940.06970.07920.3438-0.0953-0.02520.60790.22690.585559.64-91.350246.3904
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 134:157)A134 - 157
2X-RAY DIFFRACTION2(chain A and resid 158:198)A158 - 198
3X-RAY DIFFRACTION3(chain A and resid 199:219)A199 - 219
4X-RAY DIFFRACTION4(chain A and resid 220:321)A220 - 321
5X-RAY DIFFRACTION5(chain A and resid 322:382)A322 - 382
6X-RAY DIFFRACTION6(chain A and resid 383:408)A383 - 408
7X-RAY DIFFRACTION7(chain A and resid 412:480)A412 - 480
8X-RAY DIFFRACTION8(chain B and resid 136:308)B136 - 308
9X-RAY DIFFRACTION9(chain B and resid 309:427)B309 - 427
10X-RAY DIFFRACTION10(chain B and resid 428:480)B428 - 480

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