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Pustelny, K.* ; Grygier, P.* ; Barzowska, A.* ; Pucelik, B.* ; Matsuda, A.* ; Mrowiec, K.* ; Slugocka, E.* ; Popowicz, G.M. ; Dubin, G.* ; Czarna, A.*

Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics.

Sci. Rep. 13:18114 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
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The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-β inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Beta-cell Proliferation; Alzheimers-disease; Rutin Improves; Molecular Docking; Oxidative Stress; Protein-kinase; Quercetin; Gossypin; Model; Activation
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Journal Scientific Reports
Quellenangaben Volume: 13, Issue: 1, Pages: , Article Number: 18114 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants Priority Research Area BioS under the program 'Initiative of Excellence-Research University' at the Jagiellonian University in Krakow
DESY (Hamburg, Germany)
(Foundation for Polish Science)
TEAM
National Science Centre
This work was supported by a grant from the National Science Centre (UMO-2019/34/E/NZ1/00467) and by NAWA Polish Returns 2018 (PPN/PPO/2018/1/00046/U/00001) to A.C. We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE F
DOI 10.1038/s41598-023-44810-3
WOS ID 001087271600059
Scopus ID 85174731406
PubMed ID 37872245
Erfassungsdatum 2023-11-28
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