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- PDB-7zh8: DYRK1a in Complex with a Bromo-Triazolo-Pyridine -

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Basic information

Entry
Database: PDB / ID: 7zh8
TitleDYRK1a in Complex with a Bromo-Triazolo-Pyridine
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / Small Molecule / Kinase / Halogen Bond
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 / 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
6-bromanyl-3H-[1,2,3]triazolo[4,5-b]pyridine / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsDammann, M. / Stahlecker, J. / Stehle, T. / Boeckler, F.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.
Authors: Dammann, M. / Stahlecker, J. / Zimmermann, M.O. / Klett, T. / Rotzinger, K. / Kramer, M. / Coles, M. / Stehle, T. / Boeckler, F.M.
History
DepositionApr 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)185,02356
Polymers178,2134
Non-polymers6,81152
Water9,350519
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,70718
Polymers44,5531
Non-polymers2,15417
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)46,31815
Polymers44,5531
Non-polymers1,76514
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)46,26414
Polymers44,5531
Non-polymers1,71113
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)45,7349
Polymers44,5531
Non-polymers1,1818
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)245.004, 64.663, 147.308
Angle α, β, γ (deg.)90.000, 115.577, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-678-

HOH

21A-747-

HOH

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / hMNB


Mass: 44553.188 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 BL21(DE3) (bacteria) / Strain (production host): BL21pLysS / References: UniProt: Q13627, dual-specificity kinase

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Non-polymers , 10 types, 571 molecules

#2: Chemical
ChemComp-IWU / 6-bromanyl-3H-[1,2,3]triazolo[4,5-b]pyridine


Mass: 199.008 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C5H3BrN4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H14O4
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#8: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#9: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#10: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 519 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.22 Å3/Da / Density % sol: 61.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M TRIS (pH = 8.5), 0.1 M Li2SO4, 34 % (v/v) PEG300, 12 mg/ml Protein, Dropsize (resovoir + Protein) 2 + 4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 93129 / % possible obs: 99.8 % / Redundancy: 6.8 % / Biso Wilson estimate: 50.86 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.133 / Net I/σ(I): 12.48
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 1.25 / Num. unique obs: 14879 / CC1/2: 0.53 / Rrim(I) all: 1.58 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vx3

2vx3


Resolution: 2.3→48.6 Å / SU ML: 0.3699 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.9077
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2351 1487 1.6 %
Rwork0.1988 91394 -
obs0.1994 92881 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.33 Å2
Refinement stepCycle: LAST / Resolution: 2.3→48.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11175 0 387 519 12081
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009711822
X-RAY DIFFRACTIONf_angle_d1.110815926
X-RAY DIFFRACTIONf_chiral_restr0.05571660
X-RAY DIFFRACTIONf_plane_restr0.01052001
X-RAY DIFFRACTIONf_dihedral_angle_d16.26784470
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.370.3851330.30758176X-RAY DIFFRACTION99.86
2.37-2.460.34891340.31968232X-RAY DIFFRACTION99.83
2.46-2.560.37291340.28658265X-RAY DIFFRACTION99.95
2.56-2.670.28291350.24688280X-RAY DIFFRACTION99.93
2.67-2.810.30731350.23338297X-RAY DIFFRACTION99.98
2.81-2.990.25721340.24418221X-RAY DIFFRACTION99.98
2.99-3.220.25661350.20818333X-RAY DIFFRACTION99.98
3.22-3.550.23931350.18998320X-RAY DIFFRACTION100
3.55-4.060.19541360.16078340X-RAY DIFFRACTION99.93
4.06-5.110.19261360.15398362X-RAY DIFFRACTION99.98
5.11-48.60.20811400.1998568X-RAY DIFFRACTION99.78
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)
11.18721946598-0.25351989460.7010185014041.908091894420.6952069069851.663443120420.179176456198-0.2071388108160.1637696595910.0285005086380.0810559720187-0.487355559722-0.110294882420.31439735314-0.000209253724490.579678998477-0.02493179435660.03151885594230.434715269364-0.07895376343490.5498451621799.4637343152231.002585984832.448647222
21.330682762060.6372607164940.126459973162.26274240570.9226072759220.8943009395080.143852362357-0.219191202230.01206209166520.250657714345-0.0266107129348-0.118067745545-0.00828622192715-0.02927001634754.20879583563E-50.52656687377-0.02510537036790.008186659840950.343058064980.04235936273230.42565039423-1.2914544078318.991031282826.7789352439
31.49238022643-0.356672006960.04607690509951.320548115880.2724693547011.59805518230.07488653666890.0676290522043-0.004972288908060.00416323819801-0.01399301509660.090499842917-0.0832425066691-0.189448616741-0.0009622781653160.379890494387-0.009876140995470.02958692289480.2770681703130.01737943923770.389683904728-11.646829940217.41790821477.49867285839
41.26095739778-0.291316852645-0.7425207324342.49320714410.577578450041.933363154690.1996321777610.01134536594170.362400284883-0.1732065206510.101180767293-0.502660185574-0.287843280220.0913336189839-0.0001193749528170.660354465164-0.057869683410.1341447874550.413117308852-0.08585678915120.6109329059861.64344975607-12.380890399439.6470304102
52.13971923207-1.027091564320.1097341712460.698988387440.246308245981.364721345040.06054128546130.08780494330950.0903061280166-0.307426324464-0.0120718030754-0.2934343048750.001890601736420.1419225527160.0002428741221560.62228104142-0.0004771913932450.09867395181020.421437262734-0.0119217202560.494488183771-12.6685068322-5.9687170476850.9929123933
61.71929817105-0.184725975336-0.09898079471612.045842887020.01857907492161.79706441157-0.0159241279731-0.16602092248-0.03263848807560.02830599362750.0506858293717-0.03624222050650.08421153370690.0560127352473-0.001434649801480.4364064857650.01789181179290.01598074051990.425679884995-0.01716654411150.384761265845-19.6749057762-10.717490408767.066647179
70.516907603552-0.2087919130350.4588300399520.9497485142350.3340439603350.6820552779640.523457454613-0.0765485899233-0.5031690083110.102872352176-0.1464092667370.1438614327630.479670656725-0.4113583966034.27684313478E-50.784762748382-0.137076151989-0.2787627943611.13359486670.06156236249380.782270931218-55.5253811066-3.12476628334-16.5008168859
80.0141941993566-0.02204960604350.01711848842170.280857338368-0.08596598244790.1497329328740.110218159836-0.0541725736828-0.41669315755-0.3099567370540.05719461540350.2726604991160.636326777976-0.130625827866-0.0004741733762470.695984215049-0.0409184062896-0.2835995726391.04178305426-0.06979357648830.732720920119-46.4114669348-1.06761748038-20.3754168003
92.119594130680.2557972007380.1191910579550.5378999508520.401461242541.188696163340.2898510659280.225004587248-0.381924477518-0.179032673315-0.1916545109060.2884658730260.132133970948-0.496047666160.0001049797486870.568861237608-0.0904971558502-0.1239899765710.745233314520.008116221529680.655905341483-37.4404974447-1.47142907102-6.45444602638
102.284576720820.01763378607860.2290950404211.407531037910.08377544331791.84463746010.0514209750369-0.293378355441-0.1435936853920.108386530180.03440017292940.2025222813070.092180693463-0.511664645755-0.001169260626670.377285044941-0.07566454135570.0001432779568490.6200949026340.09126369858560.506948693931-33.35365377036.200751548719.25729120555
110.40409371193-0.01097796788390.09742130654510.5880083515550.4890914105930.4293141207260.3116450692540.338867792856-0.326173592242-0.2194457773730.0543863728168-0.4721415575930.1928889835990.3843022146230.0001833432378130.608703795639-0.0182760798274-0.08622492947631.383252265460.1199880982790.721232081683-49.1088563591-21.633519556425.9032600011
120.9386927748380.0008733834312820.6412457202561.345905367250.3393940085210.8651824908520.02958286004530.6705423877360.128638045773-0.309003589140.0731924942106-0.0353028276504-0.2984844373230.1454910458968.80875771624E-50.524795208602-0.122113945361-0.07054384255891.115591661620.2114655474370.574871557663-57.3508671993-5.4615137353430.8040365756
130.138656745019-0.160867031444-0.02443271785920.2099634906620.08212763267540.117344125395-0.2745595139060.263529839478-0.336852579883-0.5449601076270.2300187773250.3149023876180.163851410371-0.05476490110870.0003242670721810.56743973786-0.171469195148-0.1532800433571.070986294330.1831333477060.686633024888-67.7021786545-9.8841122122133.7022972727
140.250483665631-0.232020107043-0.03219904750520.459822065343-0.01605807710340.330823670555-0.07986101116020.1645717216140.0539431054771-0.07256958277130.08826925307330.21210539395-0.192196852183-0.09451449705390.01623280995120.467258588013-0.107176544784-0.04040945620320.7763955155680.2023092472350.574917622232-64.6249913035-5.239183879849.1049601563
150.638008980837-0.4070267825020.1357710928280.680231078130.6271308502921.26950048302-0.093511196676-0.08441161931390.2594762564920.1218725501320.07968336083860.440398367215-0.141838824964-0.641093714003-3.67915325607E-50.524981518312-0.01644029941050.0495839195110.7745510067350.1446449920960.663861055819-69.8235319671-2.2771860704460.6977053419
160.0160373125812-0.08675290890230.01032054118570.4952666865630.01312680421620.5313089257160.02011337052840.125171856990.650938656019-0.168467990627-0.04540957225930.259303061928-0.669912230334-0.20527883252-4.82717041611E-50.6936097543340.00470672715023-0.04275389438230.8080421597530.2378208662420.762692348783-62.408893092610.7975324245.5421067673
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 135 through 213 )AA135 - 2131 - 79
22chain 'A' and (resid 214 through 320 )AA214 - 32080 - 186
33chain 'A' and (resid 321 through 482 )AA321 - 482187 - 348
44chain 'B' and (resid 135 through 239 )BB135 - 2391 - 105
55chain 'B' and (resid 240 through 320 )BB240 - 320106 - 186
66chain 'B' and (resid 321 through 481 )BB321 - 481187 - 347
77chain 'C' and (resid 136 through 213 )CC136 - 2131 - 78
88chain 'C' and (resid 214 through 239 )CC214 - 23979 - 104
99chain 'C' and (resid 240 through 320 )CC240 - 320105 - 185
1010chain 'C' and (resid 321 through 481 )CC321 - 481186 - 346
1111chain 'D' and (resid 135 through 193 )DD135 - 1931 - 59
1212chain 'D' and (resid 194 through 302 )DD194 - 30260 - 168
1313chain 'D' and (resid 303 through 320 )DD303 - 320169 - 186
1414chain 'D' and (resid 321 through 377 )DD321 - 377187 - 243
1515chain 'D' and (resid 378 through 436 )DD378 - 436244 - 302
1616chain 'D' and (resid 437 through 480 )DD437 - 480303 - 346

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