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- PDB-6ln1: A natural inhibitor of DYRK1A for treatment of diabetes mellitus -

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Basic information

Entry
Database: PDB / ID: 6ln1
TitleA natural inhibitor of DYRK1A for treatment of diabetes mellitus
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / anti-diabetic activity / Desmethylbellidifolin / DYRK1A / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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
1,3,5,8-tetrakis(oxidanyl)xanthen-9-one / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.699 Å
AuthorsLi, H. / Chen, L.X. / Zheng, M.Z. / Zhang, Q.Z. / Zhang, C.L. / Wu, C.R. / Yang, K.Y. / Song, Z.R. / Wang, Q.Q. / Li, C. ...Li, H. / Chen, L.X. / Zheng, M.Z. / Zhang, Q.Z. / Zhang, C.L. / Wu, C.R. / Yang, K.Y. / Song, Z.R. / Wang, Q.Q. / Li, C. / Zhou, Y.R. / Chen, J.C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773594, 81773869, 81773637,U1803122 China
CitationJournal: Clin Transl Med / Year: 2021
Title: A natural DYRK1A inhibitor as a potential stimulator for beta-cell proliferation in diabetes.
Authors: Zheng, M. / Zhang, Q. / Zhang, C. / Wu, C. / Yang, K. / Song, Z. / Wang, Q. / Li, C. / Zhou, Y. / Chen, J. / Li, H. / Chen, L.
History
DepositionDec 28, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4784
Polymers80,9572
Non-polymers5202
Water79344
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7392
Polymers40,4791
Non-polymers2601
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)40,7392
Polymers40,4791
Non-polymers2601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)133.467, 133.467, 92.238
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63

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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: 40478.727 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 (E. coli) / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical ChemComp-EKU / 1,3,5,8-tetrakis(oxidanyl)xanthen-9-one


Mass: 260.199 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H8O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 3.02 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1M Bis-Tris, 17% PEG 1500, 30% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K / Detector: PIXEL / Date: Apr 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.699→50 Å / Num. obs: 25854 / % possible obs: 100 % / Redundancy: 10.5 % / Biso Wilson estimate: 61.94 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.031 / Rrim(I) all: 0.1 / Rsym value: 0.068 / Net I/σ(I): 22.3
Reflection shellResolution: 2.7→2.75 Å / Rmerge(I) obs: 1.196 / Mean I/σ(I) obs: 1.52 / Num. unique obs: 1304 / CC1/2: 0.731 / Rpim(I) all: 0.384 / Rrim(I) all: 1.256 / Rsym value: 1.365 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.13_2998refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YLK

4ylk


Resolution: 2.699→48.974 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 28.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2769 2015 7.8 %
Rwork0.2123 23817 -
obs0.2172 25832 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 123.42 Å2 / Biso mean: 65.7556 Å2 / Biso min: 25.89 Å2
Refinement stepCycle: final / Resolution: 2.699→48.974 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5528 0 54 44 5626
Biso mean--60.55 57.63 -
Num. residues----671
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.699-2.76630.34561440.29691703
2.7663-2.84110.34181390.28261691
2.8411-2.92470.38171450.26691672
2.9247-3.0190.28041480.25581693
3.019-3.12690.29131410.22691691
3.1269-3.25210.31881470.22861707
3.2521-3.40010.26551430.22981695
3.4001-3.57930.31391390.22631679
3.5793-3.80350.23921440.21531707
3.8035-4.0970.27161440.19751699
4.097-4.5090.25611440.18881708
4.509-5.16090.26651450.18431704
5.1609-6.49980.29151470.22311714
6.4998-48.9740.24681450.19091754

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