6cgx

From Proteopedia

(Difference between revisions)

Revision as of 10:39, 14 June 2023

Backbone cyclised conotoxin Vc1.1 mutant - D11A, E14A

Structural highlights

6cgx is a 1 chain structure with sequence from Conus victoriae. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CA1A_CONVC Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This synthetic peptide (produced without hydroxyproline, nor 4-carboxyglutamate) is a neuronal nAChR antagonist that acts as a powerful analgesic. It blocks nAChRs composed of alpha-3 or -5/beta-2 (IC(50)=7.2 uM), alpha-3/beta-2 (IC(50)=7.3 uM), alpha-3/beta-4 (IC(50)=4.2 uM), alpha-3 or -5/beta-4 (IC(50)<30 uM), alpha-4/beta-2 (IC(50)<30 uM), alpha-4/beta-4 (IC(50)<30 uM) and alpha/beta/gamma/delta (IC(50)<30 uM) subunits.^[1] ^[2]

Publication Abstract from PubMed

alpha-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several alpha-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of alpha-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore it is unclear whether activation of GABABR or inhibition of alpha9alpha10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which alpha-conotoxins provide analgesia, we synthesised a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K) and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor whereas those in the second loop play an important role for the selectivity of the peptide for the GABABR over alpha9alpha10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABABR-mediated inhibition of high voltage-activated (HVA) calcium channels over 910 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABABR-mediated HVA calcium channel inhibition by alpha-conotoxins could be effective for the treatment of chronic visceral pain.

Structure-activity studies reveal the molecular basis for GABAB-receptor mediated inhibition of high voltage-activated calcium channels by alpha-conotoxin Vc1.1.,Sadeghi M, Carstens BB, Callaghan BP, Daniel JT, Tae HS, O'Donnell T, Castro J, Brierley SM, Adams DJ, Craik DJ, Clark RJ ACS Chem Biol. 2018 May 10. doi: 10.1021/acschembio.8b00190. PMID:29746088^[3]

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

References

↑ Sandall DW, Satkunanathan N, Keays DA, Polidano MA, Liping X, Pham V, Down JG, Khalil Z, Livett BG, Gayler KR. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry. 2003 Jun 10;42(22):6904-11. PMID:12779345 doi:http://dx.doi.org/10.1021/bi034043e
↑ Lang PM, Burgstahler R, Haberberger RV, Sippel W, Grafe P. A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport. 2005 Apr 4;16(5):479-83. PMID:15770155
↑ Sadeghi M, Carstens BB, Callaghan BP, Daniel JT, Tae HS, O'Donnell T, Castro J, Brierley SM, Adams DJ, Craik DJ, Clark RJ. Structure-activity studies reveal the molecular basis for GABAB-receptor mediated inhibition of high voltage-activated calcium channels by alpha-conotoxin Vc1.1. ACS Chem Biol. 2018 May 10. doi: 10.1021/acschembio.8b00190. PMID:29746088 doi:http://dx.doi.org/10.1021/acschembio.8b00190

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/6cgx"

Categories: Conus victoriae | Large Structures | Clark RJ

@@ Line 1: / Line 1: @@
 ==Backbone cyclised conotoxin Vc1.1 mutant - D11A, E14A==
-<StructureSection load='6cgx' size='340' side='right'caption='[[6cgx]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='6cgx' size='340' side='right'caption='[[6cgx]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6cgx]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CGX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CGX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6cgx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_victoriae Conus victoriae]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CGX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CGX FirstGlance]. <br>
-</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=6cgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cgx OCA], [http://pdbe.org/6cgx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cgx RCSB], [http://www.ebi.ac.uk/pdbsum/6cgx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cgx ProSAT]</span></td></tr>
+</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=6cgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cgx OCA], [https://pdbe.org/6cgx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cgx RCSB], [https://www.ebi.ac.uk/pdbsum/6cgx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cgx ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CA1A_CONVC CA1A_CONVC]] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This synthetic peptide (produced without hydroxyproline, nor 4-carboxyglutamate) is a neuronal nAChR antagonist that acts as a powerful analgesic. It blocks nAChRs composed of alpha-3 or -5/beta-2 (IC(50)=7.2 uM), alpha-3/beta-2 (IC(50)=7.3 uM), alpha-3/beta-4 (IC(50)=4.2 uM), alpha-3 or -5/beta-4 (IC(50)<30 uM), alpha-4/beta-2 (IC(50)<30 uM), alpha-4/beta-4 (IC(50)<30 uM) and alpha/beta/gamma/delta (IC(50)<30 uM) subunits.<ref>PMID:12779345</ref> <ref>PMID:15770155</ref>
+[https://www.uniprot.org/uniprot/CA1A_CONVC CA1A_CONVC] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This synthetic peptide (produced without hydroxyproline, nor 4-carboxyglutamate) is a neuronal nAChR antagonist that acts as a powerful analgesic. It blocks nAChRs composed of alpha-3 or -5/beta-2 (IC(50)=7.2 uM), alpha-3/beta-2 (IC(50)=7.3 uM), alpha-3/beta-4 (IC(50)=4.2 uM), alpha-3 or -5/beta-4 (IC(50)<30 uM), alpha-4/beta-2 (IC(50)<30 uM), alpha-4/beta-4 (IC(50)<30 uM) and alpha/beta/gamma/delta (IC(50)<30 uM) subunits.<ref>PMID:12779345</ref> <ref>PMID:15770155</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 __TOC__
 </StructureSection>
+[[Category: Conus victoriae]]
 [[Category: Large Structures]]
-[[Category: Clark, R J]]
+[[Category: Clark RJ]]
-[[Category: Structure from molmol]]
-[[Category: Toxin]]

6cgx

From Proteopedia

Revision as of 10:39, 14 June 2023

Backbone cyclised conotoxin Vc1.1 mutant - D11A, E14A

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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