6FGC

Crystal structure of Gephyrin E domain in complex with Artesunate

6FGC の概要

• エントリーDOI: 10.2210/pdb6fgc/pdb
• 分子名称: Gephyrin, CALCIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (10 entities in total)
• 機能のキーワード: antimalarial compound, artemisinins and its derivatives, inhibitory neurotransmission, moco biosynthesis, structural protein
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47461.31

構造登録者

Kasaragod, V.B.,Schindelin, H. (登録日: 2018-01-10, 公開日: 2019-01-16, 最終更新日: 2024-01-17)

主引用文献

Kasaragod, V.B.,Hausrat, T.J.,Schaefer, N.,Kuhn, M.,Christensen, N.R.,Tessmer, I.,Maric, H.M.,Madsen, K.L.,Sotriffer, C.,Villmann, C.,Kneussel, M.,Schindelin, H.
Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins.
Neuron, 101:673-689.e11, 2019

PubMed Abstract: The frontline anti-malarial drug artemisinin and its derivatives have also been implicated in modulating multiple mammalian cellular pathways, including the recent identification of targeting γ-aminobutyric acid type A receptor (GABAR) signaling in the pancreas. Their molecular mechanism of action, however, remains elusive. Here, we present crystal structures of gephyrin, the central organizer at inhibitory postsynapses, in complex with artesunate and artemether at 1.5-Å resolution. These artemisinins target the universal inhibitory neurotransmitter receptor-binding epitope of gephyrin, thus inhibiting critical interactions between gephyrin and glycine receptors (GlyRs) as well as GABARs. Electrophysiological recordings reveal a significant inhibition of gephyrin-mediated neurotransmission by artemisinins. Furthermore, clustering analyses in primary neurons demonstrate a rapid inhibition and a time-dependent regulation of gephyrin and GABAR cluster parameters. Our data not only provide a comprehensive model for artemisinin-mediated modulation of inhibitory neurotransmission but also establish artemisinins as potential lead compounds to pharmacologically interfere with this process.

PubMed: 30704910
DOI: 10.1016/j.neuron.2019.01.001

実験手法

X-RAY DIFFRACTION (1.5 Å)