2mto
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Non-reducible analogues of alpha-conotoxin RgIA: [2,8]-cis dicarba RgIA== | |
| + | <StructureSection load='2mto' size='340' side='right'caption='[[2mto]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[2mto]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_regius Conus regius]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MTO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MTO FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</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=2mto FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mto OCA], [https://pdbe.org/2mto PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mto RCSB], [https://www.ebi.ac.uk/pdbsum/2mto PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mto ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CA1A_CONRE CA1A_CONRE] This toxin target two types of receptors, the nicotinic acetylcholine receptor (nAChR) and the G-protein-coupled receptor GABA(B). It specifically inhibits the alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR, with preference for rat receptors (PubMed:16445293, PubMed:21888386, PubMed:22774872, PubMed:25740413, PubMed:28223528, PubMed:18242183, PubMed:18295795). It interacts with the alpha-10(+)/alpha-9(-)interface of the receptor (PubMed:25740413). It shows a two order of magnitude species difference potency for the rat versus human alpha-9-alpha-10 nAChR, due to the Thr-86 located in the alpha-9 nAChR subunit (PubMed:22774872). This toxin also shows inhibition of high voltage-activated (HVA) calcium channels (Cav2.2) by acting on GABA(B) receptors (GABBR1 and GABBR2) (PubMed:18945902, PubMed:21888386). In vivo, this toxin produces an acute antinociceptive effect in peripheral nerve-injured rats, which may be related to the inhibition of immune cell buildup at the site of nerve injury (PubMed:17101979). In addition, when intramuscularly injected into rats following chronic constriction injury of the sciatic nerve, this toxin protects peripheral nervous tissues as well as prevents central maladaptive plasticity by inhibiting glial cell activation (PubMed:25008370).<ref>PMID:16445293</ref> <ref>PMID:17101979</ref> <ref>PMID:18242183</ref> <ref>PMID:18295795</ref> <ref>PMID:18945902</ref> <ref>PMID:21888386</ref> <ref>PMID:22774872</ref> <ref>PMID:25008370</ref> <ref>PMID:25740413</ref> <ref>PMID:28223528</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | alpha-Conotoxin RgIA is an antagonist of the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) subtype and also inhibits high voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with non-reducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets and stability evaluated in human serum. [3,12]-dicarba analogues retained inhibition of ACh-evoked currents at alpha9alpha10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8] dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors. | ||
| - | + | Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets.,Chhabra S, Belgi A, Bartels P, Vanlierop BJ, Robinson SD, Kompella SN, Hung A, Callaghan BP, Adams DJ, Robinson AJ, Norton RS J Med Chem. 2014 Nov 13. PMID:25393758<ref>PMID:25393758</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 2mto" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Conus regius]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chhabra S]] | ||
| + | [[Category: Norton R]] | ||
| + | [[Category: Robinson S]] | ||
Current revision
Non-reducible analogues of alpha-conotoxin RgIA: [2,8]-cis dicarba RgIA
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