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==alpha RgIA, a Novel Conotoxin that Blocks the alpha9-alpha10 nAChR==
<StructureSection load='2jur' size='340' side='right'caption='[[2jur]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2jur]] 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=2JUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JUR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=2jur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jur OCA], [https://pdbe.org/2jur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jur RCSB], [https://www.ebi.ac.uk/pdbsum/2jur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jur 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> 
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== Publication Abstract from PubMed ==
Alpha-conotoxins are small disulfide-constrained peptides from cone snails that act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide alpha-conotoxin RgIA (alpha-RgIA) is a member of the alpha-4,3 family of alpha-conotoxins and selectively blocks the alpha9alpha10 nAChR subtype, in contrast to another well-characterized member of this family, alpha-conotoxin ImI (alpha-ImI), which is a potent inhibitor of the alpha7 and alpha3beta2 nAChR subtypes. In this study, we have altered side chains in both the four-residue and the three-residue loops of alpha-RgIA, and have modified its C-terminus. The effects of these changes on activity against alpha9alpha10 and alpha7 nAChRs were measured; the solution structures of alpha-RgIA and its Y10W, D5E, and P6V analogues were determined from NMR data; and resonance assignments were made for alpha-RgIA [R9A]. The structures for alpha-RgIA and its three analogues were well defined, except at the chain termini. Comparison of these structures with reported structures of alpha-ImI reveals a common two-loop backbone architecture within the alpha-4,3 family, but with variations in side-chain solvent accessibility and orientation. Asp5, Pro6, and Arg7 in loop 1 are critical for blockade of both the alpha9alpha10 and the alpha7 subtypes. In loop 2, alpha-RgIA [Y10W] had activity near that of wild-type alpha-RgIA, with high potency for alpha9alpha10 and low potency for alpha7, and had a structure similar to that of wild type. By contrast, Arg9 in loop 2 is critical for specific binding to the alpha9alpha10 subtype, probably because it is larger and more solvent accessible than Ala9 in alpha-ImI. Our findings contribute to a better understanding of the molecular basis for antagonism of the alpha9alpha10 nAChR subtype, which is a target for the development of analgesics for the treatment of chronic neuropathic pain.

Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues.,Ellison M, Feng ZP, Park AJ, Zhang X, Olivera BM, McIntosh JM, Norton RS J Mol Biol. 2008 Apr 4;377(4):1216-27. Epub 2008 Feb 4. PMID:18295795<ref>PMID:18295795</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Conus regius]]
[[Category: Large Structures]]
[[Category: Ellison M]]
[[Category: Feng Z]]