6fgd: Difference between revisions
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==Crystal structure of Gephyrin E domain in complex with Artemether== | |||
<StructureSection load='6fgd' size='340' side='right' caption='[[6fgd]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6fgd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FGD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FGD FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=D8Z:Artemether'>D8Z</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Gphn, Gph ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fgd OCA], [http://pdbe.org/6fgd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fgd RCSB], [http://www.ebi.ac.uk/pdbsum/6fgd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fgd ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/GEPH_RAT 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.<ref>PMID:8264797</ref> <ref>PMID:9990024</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:30704910</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6fgd" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Buffalo rat]] | |||
[[Category: Kasaragod, V B]] | |||
[[Category: Schindelin, H]] | |||
[[Category: Antimalarial compound]] | |||
[[Category: Inhibitory neurotransmission]] | |||
[[Category: Moonlighting protein]] | |||
[[Category: Scaffolding protein]] | |||
[[Category: Structural protein]] | |||
Latest revision as of 11:21, 6 March 2019
Crystal structure of Gephyrin E domain in complex with ArtemetherCrystal structure of Gephyrin E domain in complex with Artemether
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] 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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