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- PDB-8hlt: The co-crystal structure of DYRK2 with YK-2-99B -

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Basic information

Entry
Database: PDB / ID: 8hlt
TitleThe co-crystal structure of DYRK2 with YK-2-99B
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 2
KeywordsCELL CYCLE / Inhibitor
Function / homology
Function and homology information


dual-specificity kinase / negative regulation of calcineurin-NFAT signaling cascade / smoothened signaling pathway / positive regulation of glycogen biosynthetic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / manganese ion binding / protein tyrosine kinase activity ...dual-specificity kinase / negative regulation of calcineurin-NFAT signaling cascade / smoothened signaling pathway / positive regulation of glycogen biosynthetic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / ubiquitin ligase complex / protein serine/threonine/tyrosine kinase activity / regulation of signal transduction by p53 class mediator / manganese ion binding / protein tyrosine kinase activity / Regulation of TP53 Activity through Phosphorylation / cytoskeleton / ribonucleoprotein complex / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / magnesium ion binding / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase / 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-XSE / Dual specificity tyrosine-phosphorylation-regulated kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsShen, H.T. / Xiao, Y.B. / Yuan, K. / Yang, P. / Li, Q.N.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31970547 China
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.
Authors: Yuan, K. / Shen, H. / Zheng, M. / Xia, F. / Li, Q. / Chen, W. / Ji, M. / Yang, H. / Zhuang, X. / Cai, Z. / Min, W. / Wang, X. / Xiao, Y. / Yang, P.
History
DepositionDec 1, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity tyrosine-phosphorylation-regulated kinase 2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,3874
Polymers90,5172
Non-polymers8712
Water00
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6942
Polymers45,2581
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6942
Polymers45,2581
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)129.820, 60.670, 155.340
Angle α, β, γ (deg.)90.00, 113.08, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Dual specificity tyrosine-phosphorylation-regulated kinase 2


Mass: 45258.262 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92630, dual-specificity kinase
#2: Chemical ChemComp-XSE / (6-{[(4P)-4-(1,3-benzothiazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pyridin-3-yl)(piperazin-1-yl)methanone


Mass: 435.477 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18FN7OS
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: 3.17 Å3/Da / Density % sol: 61.17 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop
Details: 0.05M HEPES pH7.0, 12%PEG 3350, 1% Trptone, 1mM NaN3

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Data collection

DiffractionMean temperature: 289.15 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 31, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.74→47.85 Å / Num. obs: 29520 / % possible obs: 99.8 % / Redundancy: 6.7 % / CC1/2: 0.996 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.051 / Rrim(I) all: 0.132 / Χ2: 0.98 / Net I/σ(I): 9.9 / Num. measured all: 198388
Reflection shellResolution: 2.74→2.81 Å / % possible obs: 100 % / Redundancy: 7 % / Rmerge(I) obs: 1.017 / Num. measured all: 14840 / Num. unique obs: 2126 / CC1/2: 0.871 / Rpim(I) all: 0.41 / Rrim(I) all: 1.098 / Χ2: 0.89 / Net I/σ(I) obs: 2

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Processing

Software
NameVersionClassification
XDSdata scaling
PHENIX19refinement
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→47.85 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2669 1860 6.71 %
Rwork0.2092 --
obs0.2131 27702 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→47.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6240 0 62 0 6302
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.016460
X-RAY DIFFRACTIONf_angle_d1.2558710
X-RAY DIFFRACTIONf_dihedral_angle_d15.5092456
X-RAY DIFFRACTIONf_chiral_restr0.065900
X-RAY DIFFRACTIONf_plane_restr0.0111124
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.880.37141340.30912023X-RAY DIFFRACTION100
2.88-2.960.33351370.27581916X-RAY DIFFRACTION100
2.96-3.060.28281460.25311972X-RAY DIFFRACTION100
3.06-3.170.30511410.25381973X-RAY DIFFRACTION100
3.17-3.290.31711440.24541969X-RAY DIFFRACTION100
3.29-3.440.31061350.22281980X-RAY DIFFRACTION100
3.44-3.620.28341480.21981981X-RAY DIFFRACTION100
3.62-3.850.28371430.22181996X-RAY DIFFRACTION100
3.85-4.150.27481400.20781978X-RAY DIFFRACTION100
4.15-4.560.2541520.18231977X-RAY DIFFRACTION100
4.56-5.220.23681420.17612007X-RAY DIFFRACTION100
5.22-6.580.25231480.21252033X-RAY DIFFRACTION100
6.58-47.850.23491500.19152037X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: -17.4588 Å / Origin y: -11.7727 Å / Origin z: 31.4546 Å
111213212223313233
T0.5654 Å20.0911 Å20.1476 Å2-0.4255 Å2-0.0406 Å2--0.6418 Å2
L3.4139 °2-0.102 °20.9498 °2-0.6713 °2-0.3076 °2--0.9963 °2
S0.0137 Å °-0.5422 Å °0.2584 Å °0.0639 Å °-0.0123 Å °0.1291 Å °-0.0611 Å °-0.149 Å °-0.0121 Å °
Refinement TLS groupSelection details: all

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