2jur

From Proteopedia

(Difference between revisions)

Revision as of 13:07, 26 July 2023

alpha RgIA, a Novel Conotoxin that Blocks the alpha9-alpha10 nAChR

Structural highlights

2jur is a 1 chain structure with sequence from Conus regius. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

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^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ellison M, Haberlandt C, Gomez-Casati ME, Watkins M, Elgoyhen AB, McIntosh JM, Olivera BM. Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR. Biochemistry. 2006 Feb 7;45(5):1511-7. PMID:16445293 doi:http://dx.doi.org/10.1021/bi0520129
↑ Vincler M, Wittenauer S, Parker R, Ellison M, Olivera BM, McIntosh JM. Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17880-4. doi:, 10.1073/pnas.0608715103. Epub 2006 Nov 13. PMID:17101979 doi:http://dx.doi.org/10.1073/pnas.0608715103
↑ Clark RJ, Daly NL, Halai R, Nevin ST, Adams DJ, Craik DJ. The three-dimensional structure of the analgesic alpha-conotoxin, RgIA. FEBS Lett. 2008 Mar 5;582(5):597-602. doi: 10.1016/j.febslet.2008.01.027. Epub, 2008 Jan 31. PMID:18242183 doi:http://dx.doi.org/10.1016/j.febslet.2008.01.027
↑ Ellison M, Feng ZP, Park AJ, Zhang X, Olivera BM, McIntosh JM, Norton RS. Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol. 2008 Apr 4;377(4):1216-27. Epub 2008 Feb 4. PMID:18295795 doi:10.1016/j.jmb.2008.01.082
↑ Callaghan B, Haythornthwaite A, Berecki G, Clark RJ, Craik DJ, Adams DJ. Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J Neurosci. 2008 Oct 22;28(43):10943-51. doi: 10.1523/JNEUROSCI.3594-08.2008. PMID:18945902 doi:http://dx.doi.org/10.1523/JNEUROSCI.3594-08.2008
↑ Halai R, Callaghan B, Daly NL, Clark RJ, Adams DJ, Craik DJ. Effects of cyclization on stability, structure, and activity of alpha-conotoxin RgIA at the alpha9alpha10 nicotinic acetylcholine receptor and GABA(B) receptor. J Med Chem. 2011 Oct 13;54(19):6984-92. doi: 10.1021/jm201060r. Epub 2011 Sep 15. PMID:21888386 doi:http://dx.doi.org/10.1021/jm201060r
↑ Azam L, McIntosh JM. Molecular basis for the differential sensitivity of rat and human alpha9alpha10 nAChRs to alpha-conotoxin RgIA. J Neurochem. 2012 Sep;122(6):1137-44. doi: 10.1111/j.1471-4159.2012.07867.x. Epub, 2012 Aug 3. PMID:22774872 doi:http://dx.doi.org/10.1111/j.1471-4159.2012.07867.x
↑ Di Cesare Mannelli L, Cinci L, Micheli L, Zanardelli M, Pacini A, McIntosh JM, Ghelardini C. alpha-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement. Pain. 2014 Oct;155(10):1986-95. doi: 10.1016/j.pain.2014.06.023. Epub 2014 Jul 5. PMID:25008370 doi:http://dx.doi.org/10.1016/j.pain.2014.06.023
↑ Azam L, Papakyriakou A, Zouridakis M, Giastas P, Tzartos SJ, McIntosh JM. Molecular interaction of alpha-conotoxin RgIA with the rat alpha9alpha10 nicotinic acetylcholine receptor. Mol Pharmacol. 2015 May;87(5):855-64. doi: 10.1124/mol.114.096511. Epub 2015 Mar , 4. PMID:25740413 doi:http://dx.doi.org/10.1124/mol.114.096511
↑ Romero HK, Christensen SB, Di Cesare Mannelli L, Gajewiak J, Ramachandra R, Elmslie KS, Vetter DE, Ghelardini C, Iadonato SP, Mercado JL, Olivera BM, McIntosh JM. Inhibition of alpha9alpha10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):E1825-E1832. doi:, 10.1073/pnas.1621433114. Epub 2017 Feb 21. PMID:28223528 doi:http://dx.doi.org/10.1073/pnas.1621433114
↑ Ellison M, Feng ZP, Park AJ, Zhang X, Olivera BM, McIntosh JM, Norton RS. Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol. 2008 Apr 4;377(4):1216-27. Epub 2008 Feb 4. PMID:18295795 doi:10.1016/j.jmb.2008.01.082

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2jur"

Categories: Conus regius | Large Structures | Ellison M | Feng Z

@@ Line 1: / Line 1: @@
 ==alpha RgIA, a Novel Conotoxin that Blocks the alpha9-alpha10 nAChR==
-<StructureSection load='2jur' size='340' side='right'caption='[[2jur]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2jur' size='340' side='right'caption='[[2jur]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2jur]] is a 1 chain structure. 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>
+<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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2juq|2juq]], [[2jus|2jus]], [[2jut|2jut]]</div></td></tr>
+</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='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/CXA1A_CONRE CXA1A_CONRE]] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. Is a specific blocker of the alpha-9/alpha-10 nAChR. Is also active on alpha-7 (but 1000-fold less potent) and on alpha-2/beta-2, alpha-2/beta-4, alpha-3/beta-4, alpha-3/beta-2, alpha-4/beta-2, alpha-4/beta-4 and alpha-6 or -3/beta-2 or -3 (but 2000-fold less potent) channels.<ref>PMID:16445293</ref>
+[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 ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Conus regius]]
 [[Category: Large Structures]]
-[[Category: Ellison, M]]
+[[Category: Ellison M]]
-[[Category: Feng, Z]]
+[[Category: Feng Z]]
-[[Category: Disulfide bond]]
-[[Category: Signaling protein inhibitor]]
-[[Category: Toxin]]
-[[Category: Two-loop backbone architecture]]

2jur

From Proteopedia

Revision as of 13:07, 26 July 2023

alpha RgIA, a Novel Conotoxin that Blocks the alpha9-alpha10 nAChR

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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