7U36

Crystal structure of human GSK3B in complex with ARN1484

7U36 の概要

• エントリーDOI: 10.2210/pdb7u36/pdb
• 分子名称: Glycogen synthase kinase-3 beta, CHLORIDE ION, (3S)-1-[(2-fluorophenoxy)acetyl]-N-(pyridin-2-yl)pyrrolidine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80619.45

構造登録者

Tripathi, S.K.,Balboni, B.,Giabbai, B.,Storici, P.,Girotto, S.,Cavalli, A. (登録日: 2022-02-25, 公開日: 2022-04-27, 最終更新日: 2023-10-18)

主引用文献

Balboni, B.,Tripathi, S.K.,Veronesi, M.,Russo, D.,Penna, I.,Giabbai, B.,Bandiera, T.,Storici, P.,Girotto, S.,Cavalli, A.
Identification of Novel GSK-3 beta Hits Using Competitive Biophysical Assays.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer's disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.

PubMed: 35409221
DOI: 10.3390/ijms23073856

実験手法

X-RAY DIFFRACTION (2.75 Å)