View source for 5ug5


==NMR SOLUTION STRUCTURE OF THE ALPHA-CONOTOXIN GID MUTANT V13Y==
<StructureSection load='5ug5' size='340' side='right'caption='[[5ug5]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ug5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_geographus Conus geographus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UG5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</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=5ug5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ug5 OCA], [https://pdbe.org/5ug5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ug5 RCSB], [https://www.ebi.ac.uk/pdbsum/5ug5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ug5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CA1D_CONGE CA1D_CONGE] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This toxin reversibly blocks alpha-3-beta-2 (IC(50)=3.1-5.1 nM), alpha-7 (IC(50)=4.5-5.1 nM), and alpha-4-beta-2 (IC(50)=128.6-390 nM) nAChRs.<ref>PMID:12419800</ref> <ref>PMID:15929983</ref> <ref>PMID:19098004</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the alpha4beta2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin alpha-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock alpha-GID and its analogs to an alpha4beta2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive alpha-GID mutants (alpha-GID[A10V], alpha-GID[V13I], and alpha-GID[V13Y]) and one inactive variant (alpha-GID[A10Q]). Two mutants, alpha-GID[A10V] and alpha-GID[V13Y], had substantially reduced potency at the human alpha7 nAChR relative to alpha-GID, a desirable feature for alpha-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the alpha-GID:alpha4beta2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.,Leffler AE, Kuryatov A, Zebroski HA, Powell SR, Filipenko P, Hussein AK, Gorson J, Heizmann A, Lyskov S, Tsien RW, Poget SF, Nicke A, Lindstrom J, Rudy B, Bonneau R, Holford M Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8100-E8109. doi:, 10.1073/pnas.1703952114. Epub 2017 Sep 5. PMID:28874590<ref>PMID:28874590</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ug5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Conus geographus]]
[[Category: Large Structures]]
[[Category: Bonneau R]]
[[Category: Filipenko P]]
[[Category: Gorson J]]
[[Category: Heizmann A]]
[[Category: Holford M]]
[[Category: Hussein A]]
[[Category: Kuryatov A]]
[[Category: Leffler AE]]
[[Category: Lindstrom J]]
[[Category: Lyskov S]]
[[Category: Nicke A]]
[[Category: Poget SF]]
[[Category: Powell SR]]
[[Category: Rudy B]]
[[Category: Zebroski HA]]