6fgd

Crystal structure of Gephyrin E domain in complex with ArtemetherCrystal structure of Gephyrin E domain in complex with Artemether

Structural highlights

6fgd is a 1 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Gene:	Gphn, Gph (Buffalo rat)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

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 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

↑ Kirsch J, Wolters I, Triller A, Betz H. Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature. 1993 Dec 23-30;366(6457):745-8. PMID:8264797 doi:http://dx.doi.org/10.1038/366745a0
↑ Stallmeyer B, Schwarz G, Schulze J, Nerlich A, Reiss J, Kirsch J, Mendel RR. The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1333-8. PMID:9990024
↑ Kasaragod VB, Hausrat TJ, Schaefer N, Kuhn M, Christensen NR, Tessmer I, Maric HM, Madsen KL, Sotriffer C, Villmann C, Kneussel M, Schindelin H. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. Neuron. 2019 Jan 15. pii: S0896-6273(19)30002-9. doi:, 10.1016/j.neuron.2019.01.001. PMID:30704910 doi:http://dx.doi.org/10.1016/j.neuron.2019.01.001

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OCA

[1] Kirsch J, Wolters I, Triller A, Betz H. Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature. 1993 Dec 23-30;366(6457):745-8. PMID:8264797 doi:http://dx.doi.org/10.1038/366745a0

[2] Stallmeyer B, Schwarz G, Schulze J, Nerlich A, Reiss J, Kirsch J, Mendel RR. The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1333-8. PMID:9990024

[3] Kasaragod VB, Hausrat TJ, Schaefer N, Kuhn M, Christensen NR, Tessmer I, Maric HM, Madsen KL, Sotriffer C, Villmann C, Kneussel M, Schindelin H. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. Neuron. 2019 Jan 15. pii: S0896-6273(19)30002-9. doi:, 10.1016/j.neuron.2019.01.001. PMID:30704910 doi:http://dx.doi.org/10.1016/j.neuron.2019.01.001

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