6FGD

Crystal structure of Gephyrin E domain in complex with Artemether

Summary for 6FGD

• Entry DOI: 10.2210/pdb6fgd/pdb
• Descriptor: Gephyrin, CALCIUM ION, PHOSPHATE ION, ... (9 entities in total)
• Functional Keywords: antimalarial compound, scaffolding protein, moonlighting protein, inhibitory neurotransmission, structural protein
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 48111.32

Authors

Kasaragod, V.B.,Schindelin, H. (deposition date: 2018-01-10, release date: 2019-01-16, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.5 Å)