6hsn | pdb_00006hsn
Crystal structure of the ternary complex of GephE-ADP-GABA(A) receptor derived peptide
Structural highlights
Function[GEPH_RAT] Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules (By similarity). Catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released.[1] [2] [GBRA3_RAT] GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Publication Abstract from PubMedThe frontline anti-malarial drug artemisinin and its derivatives have also been implicated in modulating multiple mammalian cellular pathways, including the recent identification of targeting gamma-aminobutyric acid type A receptor (GABAAR) 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-A 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 GABAARs. 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 GABAAR 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. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins.,Kasaragod VB, Hausrat TJ, Schaefer N, Kuhn M, Christensen NR, Tessmer I, Maric HM, Madsen KL, Sotriffer C, Villmann C, Kneussel M, Schindelin H Neuron. 2019 Jan 15. pii: S0896-6273(19)30002-9. doi:, 10.1016/j.neuron.2019.01.001. PMID:30704910[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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