6GN1

Crystal Structure of Glycogen synthase kinase-3 beta (GSK3B) in Complex with PIK-75

6GN1 の概要

• エントリーDOI: 10.2210/pdb6gn1/pdb
• 分子名称: Glycogen synthase kinase-3 beta, CHLORIDE ION, ~{N}-[(~{E})-(6-bromanylimidazo[1,2-a]pyridin-3-yl)methylideneamino]-~{N},2-dimethyl-5-nitro-benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: glycogen synthase kinase-3 beta, pik-75, halogen bond, inhibitor, transferase
• 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: 84316.83

構造登録者

Tesch, R.,Becker, C.,Mueller, M.P.,Sant'Anna, C.M.R.,Fraga, C.A.M.,Rauh, D. (登録日: 2018-05-29, 公開日: 2018-06-20, 最終更新日: 2024-10-09)

主引用文献

Tesch, R.,Becker, C.,Muller, M.P.,Beck, M.E.,Quambusch, L.,Getlik, M.,Lategahn, J.,Uhlenbrock, N.,Costa, F.N.,Poleto, M.D.,Pinheiro, P.S.M.,Rodrigues, D.A.,Sant'Anna, C.M.R.,Ferreira, F.F.,Verli, H.,Fraga, C.A.M.,Rauh, D.
An Unusual Intramolecular Halogen Bond Guides Conformational Selection.
Angew. Chem. Int. Ed. Engl., 57:9970-9975, 2018

PubMed Abstract: PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure-activity relationship data show the importance of the NO and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.

PubMed: 29873877
DOI: 10.1002/anie.201804917

実験手法

X-RAY DIFFRACTION (2.6 Å)