9baf
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Solution NMR structure of conofurin-Delta== | |
| + | <StructureSection load='9baf' size='340' side='right'caption='[[9baf]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9baf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_lividus Conus lividus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9BAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BAF FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9baf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9baf OCA], [https://pdbe.org/9baf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9baf RCSB], [https://www.ebi.ac.uk/pdbsum/9baf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9baf ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CA1A_CONLI CA1A_CONLI] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This toxin blocks alpha-3-beta-2/CHRNA3-CHRNB2 nAChR with high selectivity (IC(50)=8.67 nM (on rat) and 17.5 (on human)) (PubMed:24398291). Has also weaker activity on alpha-6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC(50)=108 nM (on rat)), alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) (IC(50)=121 nM (on rat)), alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=148 nM (on rat)), and alpha-7/CHRNA7 nAChRs (IC(50)=3000 nM (on rat)) (PubMed:24398291). When tested on mouse with hot-plate tests, this toxin significantly increases the base pain threshold and shows analgesic effects (PubMed:26742048).<ref>PMID:24398291</ref> <ref>PMID:26742048</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence ((682)RRARS(686)) that forms a cleavage site for the enzyme furin. Strikingly, the structure of the spike-protein loop containing the furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the furin cleavage-sites of wild-type (B.1 variant) SARS-CoV-2 or the Alpha, Delta, and Omicron variants. Remarkably, some of these peptides potently inhibited alpha7 and alpha9alpha10 nicotinic acetylcholine receptors (nAChR) with nM affinity and showed SARS-CoV-2 variant and nAChR subtype-dependent potencies. Nuclear magnetic resonance spectroscopy and molecular dynamics were used to rationalize structure-activity relationships between peptides and their cognate receptors. These findings delineate nAChR subtypes that can serve as high-affinity spike-protein targets in tissues central to COVID-19 pathophysiology and identify ligands and target receptors to inform the development of novel SARS-CoV-2 therapeutics. | ||
| - | + | Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors.,Hone AJ, Santiago U, Harvey PJ, Tekarli B, Gajewiak J, Craik DJ, Camacho CJ, McIntosh JM J Med Chem. 2024 Jun 13;67(11):9587-9598. doi: 10.1021/acs.jmedchem.4c00735. Epub , 2024 May 30. PMID:38814877<ref>PMID:38814877</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9baf" style="background-color:#fffaf0;"></div> |
| - | [[Category: Craik | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Conus lividus]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Craik DJ]] | ||
| + | [[Category: Harvey PJ]] | ||
| + | [[Category: Hone AJ]] | ||
| + | [[Category: McIntosh JM]] | ||
Revision as of 07:23, 3 July 2024
Solution NMR structure of conofurin-Delta
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