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- PDB-6uip: DYRK1A Kinase Domain in Complex with a 6-azaindole Derivative, GN... -

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Basic information

Entry
Database: PDB / ID: 6uip
TitleDYRK1A Kinase Domain in Complex with a 6-azaindole Derivative, GNF2133.
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE / Kinase / 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 mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator ...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 mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 / tau protein binding / non-membrane spanning protein tyrosine kinase activity / 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-Q8J / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.7 Å
AuthorsDiDonato, M. / Spraggon, G.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.
Authors: Liu, Y.A. / Jin, Q. / Zou, Y. / Ding, Q. / Yan, S. / Wang, Z. / Hao, X. / Nguyen, B. / Zhang, X. / Pan, J. / Mo, T. / Jacobsen, K. / Lam, T. / Wu, T.Y. / Petrassi, H.M. / Bursulaya, B. / ...Authors: Liu, Y.A. / Jin, Q. / Zou, Y. / Ding, Q. / Yan, S. / Wang, Z. / Hao, X. / Nguyen, B. / Zhang, X. / Pan, J. / Mo, T. / Jacobsen, K. / Lam, T. / Wu, T.Y. / Petrassi, H.M. / Bursulaya, B. / DiDonato, M. / Gordon, W.P. / Liu, B. / Baaten, J. / Hill, R. / Nguyen-Tran, V. / Qiu, M. / Zhang, Y.Q. / Kamireddy, A. / Espinola, S. / Deaton, L. / Ha, S. / Harb, G. / Jia, Y. / Li, J. / Shen, W. / Schumacher, A.M. / Colman, K. / Glynne, R. / Pan, S. / McNamara, P. / Laffitte, B. / Meeusen, S. / Molteni, V. / Loren, J.
History
DepositionOct 1, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 11, 2023Group: 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 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,5486
Polymers126,2453
Non-polymers1,3043
Water0
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5162
Polymers42,0821
Non-polymers4351
Water0
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)42,5162
Polymers42,0821
Non-polymers4351
Water0
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)42,5162
Polymers42,0821
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)112.884, 112.884, 304.651
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number151
Space group name H-MP3112
Space group name HallP312(x,y,z+1/3)
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: -y,-x,-z+2/3
#5: -x+y,y,-z+1/3
#6: x,x-y,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31
12
22
32

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain 'A' and (resid 136 through 154 or resid 159...A136 - 153
121(chain 'A' and (resid 136 through 154 or resid 159...A159 - 177
131(chain 'A' and (resid 136 through 154 or resid 159...A184 - 212
141(chain 'A' and (resid 136 through 154 or resid 159...A221 - 222
151(chain 'A' and (resid 136 through 154 or resid 159...A226 - 278
161(chain 'A' and (resid 136 through 154 or resid 159...A283 - 297
171(chain 'A' and (resid 136 through 154 or resid 159...A301 - 308
181(chain 'A' and (resid 136 through 154 or resid 159...A321 - 407
191(chain 'A' and (resid 136 through 154 or resid 159...A413 - 438
1101(chain 'A' and (resid 136 through 154 or resid 159...A446 - 476
211(chain 'B' and (resid 136 through 154 or resid 159...B136 - 153
221(chain 'B' and (resid 136 through 154 or resid 159...B159 - 177
231(chain 'B' and (resid 136 through 154 or resid 159...B184 - 212
241(chain 'B' and (resid 136 through 154 or resid 159...B221 - 222
251(chain 'B' and (resid 136 through 154 or resid 159...B226 - 278
261(chain 'B' and (resid 136 through 154 or resid 159...B283 - 297
271(chain 'B' and (resid 136 through 154 or resid 159...B301 - 308
281(chain 'B' and (resid 136 through 154 or resid 159...B321 - 407
291(chain 'B' and (resid 136 through 154 or resid 159...B413 - 438
2101(chain 'B' and (resid 136 through 154 or resid 159...B446 - 476
311(chain 'C' and (resid 136 through 298 or resid 301 through 477))C136 - 153
321(chain 'C' and (resid 136 through 298 or resid 301 through 477))C159 - 177
331(chain 'C' and (resid 136 through 298 or resid 301 through 477))C184 - 212
341(chain 'C' and (resid 136 through 298 or resid 301 through 477))C221 - 222
351(chain 'C' and (resid 136 through 298 or resid 301 through 477))C226 - 278
361(chain 'C' and (resid 136 through 298 or resid 301 through 477))C283 - 297
371(chain 'C' and (resid 136 through 298 or resid 301 through 477))C301 - 308
381(chain 'C' and (resid 136 through 298 or resid 301 through 477))C321 - 407
391(chain 'C' and (resid 136 through 298 or resid 301 through 477))C413 - 438
3101(chain 'C' and (resid 136 through 298 or resid 301 through 477))C446 - 476
112chain 'L'L1
212chain 'M'M1
312chain 'N'N1

NCS ensembles :
ID
1
2

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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: 42081.535 Da / Num. of mol.: 3
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) / Variant (production host): RIPL / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-Q8J / 4-ethyl-N-{4-[1-(oxan-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]pyridin-2-yl}piperazine-1-carboxamide


Mass: 434.534 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H30N6O2 / Feature type: SUBJECT OF INVESTIGATION
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: 4.45 Å3/Da / Density % sol: 72 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 15% PEG 20000, 3% Eextran Sulfate, 100 mM Bicine pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 17, 2014
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97648 Å / Relative weight: 1
ReflectionResolution: 3.7→48.26 Å / Num. obs: 23849 / % possible obs: 98.48 % / Redundancy: 8.4 % / Biso Wilson estimate: 24.87 Å2 / Rpim(I) all: 0.048 / Rrim(I) all: 0.122 / Χ2: 0.987 / Net I/σ(I): 24.9
Reflection shellResolution: 3.7→3.83 Å / Redundancy: 8.4 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2168 / CC1/2: 0.865 / Rpim(I) all: 0.58 / Χ2: 1.018 / % possible all: 86.14

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2VX3

2vx3


Resolution: 3.7→48.26 Å / SU ML: 0.2943 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.9137
Details: NCS restraints were used in phenix along with grouped B factor refinement.
RfactorNum. reflection% reflectionSelection details
Rfree0.2904 1155 4.87 %Random
Rwork0.2714 ---
obs0.2724 23736 98.54 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 48.08 Å2
Refinement stepCycle: LAST / Resolution: 3.7→48.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8107 0 96 0 8203
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038397
X-RAY DIFFRACTIONf_angle_d0.64111321
X-RAY DIFFRACTIONf_chiral_restr0.0441200
X-RAY DIFFRACTIONf_plane_restr0.0041495
X-RAY DIFFRACTIONf_dihedral_angle_d5.13555098
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.7-3.870.38331330.3632531X-RAY DIFFRACTION88.89
3.87-4.080.30741340.28682850X-RAY DIFFRACTION99.87
4.08-4.330.30481390.26172840X-RAY DIFFRACTION100
4.33-4.670.25371390.24412834X-RAY DIFFRACTION100
4.67-5.130.23231690.23912843X-RAY DIFFRACTION100
5.13-5.880.30351650.27552808X-RAY DIFFRACTION100
5.88-7.40.26631280.2672911X-RAY DIFFRACTION100
7.4-48.260.28411480.25232964X-RAY DIFFRACTION99.55
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)
10.1018721209630.00839605364470.03476444810460.138332343987-0.02341157217130.1163603543220.1822233570890.4298489854970.24519318829-0.2805755793710.03379835750450.249249711388-0.335071734007-0.3683796300220.09085162387530.4194648833590.373885430971-0.0388011345671-0.2425495163470.260548639270.25623834101349.8554111198-8.6805150290831.9615104145
20.1476720714560.0463440431518-0.04293436225870.0861516880916-0.02904447180530.180332762446-0.01942663037070.08096657336980.203965479992-0.08373115707980.219877277396-0.2084652257860.07673674511030.7234110344330.3539812856780.4874910196520.491996808757-0.3038260209360.708283949792-0.1133618662770.34755827999193.1069540684-44.808033906428.9478386569
30.01360547202550.00800265964371-0.04517804529550.0268049164237-0.02446910518590.01778366560660.0208825953594-0.168045993627-0.2116188439110.2858772767810.005271975645960.5393209654280.6145037944120.05854561312820.0648286902321.42182338510.8188087003710.133065014880.05781033318160.06926700789960.8096206733475.2695124174-61.951123649557.8761050918
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A or chain L
2X-RAY DIFFRACTION2chain B or chain M
3X-RAY DIFFRACTION3chain C or chain N

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