4x9z

From Proteopedia

(Difference between revisions)

Current revision

Dimeric conotoxin alphaD-GeXXA

Structural highlights

4x9z is a 2 chain structure with sequence from Conus generalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.5Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CDKA_CONGR Alpha-D-conopeptides act as non-competitive inhibitors of nicotinic acetylcholine receptors (nAChR). Through its two C-terminal domains, this homodimeric protein would bind to two nAChR allosteric sites, located outside the nAChR C-loop of the principal binding face and at the adjacent binding interface in a clockwise direction (By similarity). This toxin has strong inhibitory activity on rat alpha-9-alpha-10 (CHRNA9-CHRNA10) (IC(50)=1.2 nM) and a moderate inhibitory activity on human alpha-7 (CHRNA7) (IC(50)=210 nM), rat alpha-3-beta-2 (CHRNA3-CHRNB2) (IC(50)=498 nM), rat alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=614 nM) and rat alpha-1-beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRNE-CHRND) (IC(50)=743 nM) subtypes (PubMed:26395518). Shows a weaker inhibitory activity on human alpha-9-alpha-10 (IC(50)=28 nM) than on the rat channel (PubMed:26395518). This is explained by a different residue in the probable binding site (His-31 in rat alpha-10 and Leu-31 in human) (PubMed:26395518).[UniProtKB:P0C1W6]^[1]

Publication Abstract from PubMed

Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting alphaD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of alphaD-GeXXA, GeXXA-CTD, retains inhibitory activity against the alpha9alpha10 nAChR subtype. Furthermore, we identified that His7 of the rat alpha10 nAChR subunit determines the species preference of alphaD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that alphaD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of alphaD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.

Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors.,Xu S, Zhang T, Kompella SN, Yan M, Lu A, Wang Y, Shao X, Chi C, Adams DJ, Ding J, Wang C Sci Rep. 2015 Sep 23;5:14261. doi: 10.1038/srep14261. PMID:26395518^[2]

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

References

↑ Xu S, Zhang T, Kompella SN, Yan M, Lu A, Wang Y, Shao X, Chi C, Adams DJ, Ding J, Wang C. Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors. Sci Rep. 2015 Sep 23;5:14261. doi: 10.1038/srep14261. PMID:26395518 doi:http://dx.doi.org/10.1038/srep14261
↑ Xu S, Zhang T, Kompella SN, Yan M, Lu A, Wang Y, Shao X, Chi C, Adams DJ, Ding J, Wang C. Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors. Sci Rep. 2015 Sep 23;5:14261. doi: 10.1038/srep14261. PMID:26395518 doi:http://dx.doi.org/10.1038/srep14261

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/4x9z"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4x9z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_generalis Conus generalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X9Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X9Z FirstGlance]. <br>
-</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=4x9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x9z OCA], [https://pdbe.org/4x9z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x9z RCSB], [https://www.ebi.ac.uk/pdbsum/4x9z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x9z ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</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=4x9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x9z OCA], [https://pdbe.org/4x9z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x9z RCSB], [https://www.ebi.ac.uk/pdbsum/4x9z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x9z ProSAT]</span></td></tr>
 </table>
 == Function ==
-[https://www.uniprot.org/uniprot/CDKA_CONGR CDKA_CONGR] Alpha-D-conopeptides act as non-competitive inhibitors of nicotinic acetylcholine receptors (nAChR). This toxin has strong inhibitory activity on rat alpha-9-alpha-10 (CHRNA9-CHRNA10) (IC(50)=1.2 nM) and a moderate inhibitory activity on human alpha-7 (CHRNA7) (IC(50)=210 nM), rat alpha-3-beta-2 (CHRNA3-CHRNB2) (IC(50)=498 nM), rat alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=614 nM) and rat alpha-1-beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRNE-CHRND) (IC(50)=743 nM) subtypes. Shows a weaker inhibitory activity on human alpha-9-alpha-10 (IC(50)=28 nM) than on the rat channel. This is explained by a different residue in the probable binding site (His-31 in rat alpha-10 and Leu-31 in human).<ref>PMID:26395518</ref>
+[https://www.uniprot.org/uniprot/CDKA_CONGR CDKA_CONGR] Alpha-D-conopeptides act as non-competitive inhibitors of nicotinic acetylcholine receptors (nAChR). Through its two C-terminal domains, this homodimeric protein would bind to two nAChR allosteric sites, located outside the nAChR C-loop of the principal binding face and at the adjacent binding interface in a clockwise direction (By similarity). This toxin has strong inhibitory activity on rat alpha-9-alpha-10 (CHRNA9-CHRNA10) (IC(50)=1.2 nM) and a moderate inhibitory activity on human alpha-7 (CHRNA7) (IC(50)=210 nM), rat alpha-3-beta-2 (CHRNA3-CHRNB2) (IC(50)=498 nM), rat alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=614 nM) and rat alpha-1-beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRNE-CHRND) (IC(50)=743 nM) subtypes (PubMed:26395518). Shows a weaker inhibitory activity on human alpha-9-alpha-10 (IC(50)=28 nM) than on the rat channel (PubMed:26395518). This is explained by a different residue in the probable binding site (His-31 in rat alpha-10 and Leu-31 in human) (PubMed:26395518).[UniProtKB:P0C1W6]<ref>PMID:26395518</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

4x9z

From Proteopedia

Current revision

Dimeric conotoxin alphaD-GeXXA

Structural highlights

Function

Publication Abstract from PubMed

References

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