2bc7
From Proteopedia
(New page: 200px<br /><applet load="2bc7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2bc7" /> '''Solution structure of [Sec2,8]-ImI'''<br /> ...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2bc7.gif|left|200px]]<br /><applet load="2bc7" size=" | + | [[Image:2bc7.gif|left|200px]]<br /><applet load="2bc7" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2bc7" /> | caption="2bc7" /> | ||
'''Solution structure of [Sec2,8]-ImI'''<br /> | '''Solution structure of [Sec2,8]-ImI'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Disulfide bonds are important structural motifs that play an essential | + | Disulfide bonds are important structural motifs that play an essential role in maintaining the conformational stability of many bioactive peptides. Of particular importance are the conotoxins, which selectively target a wide range of ion channels that are implicated in numerous disease states. Despite the enormous potential of conotoxins as therapeutics, their multiple disulfide bond frameworks are inherently unstable under reducing conditions. Reduction or scrambling by thiol-containing molecules such as glutathione or serum albumin in intracellular or extracellular environments such as blood plasma can decrease their effectiveness as drugs. To address this issue, we describe a new class of selenoconotoxins where cysteine residues are replaced by selenocysteine to form isosteric and nonreducible diselenide bonds. Three isoforms of alpha-conotoxin ImI were synthesized by t-butoxycarbonyl chemistry with systematic replacement of one ([Sec(2,8)]ImI or [Sec(3,12)]ImI), or both ([Sec(2,3,8,12)]ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the alpha7 nicotinic acetylcholine receptor, with each selenoanalogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs. |
==About this Structure== | ==About this Structure== | ||
| - | 2BC7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http:// | + | 2BC7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BC7 OCA]. |
==Reference== | ==Reference== | ||
Alpha-selenoconotoxins, a new class of potent alpha7 neuronal nicotinic receptor antagonists., Armishaw CJ, Daly NL, Nevin ST, Adams DJ, Craik DJ, Alewood PF, J Biol Chem. 2006 May 19;281(20):14136-43. Epub 2006 Feb 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16500898 16500898] | Alpha-selenoconotoxins, a new class of potent alpha7 neuronal nicotinic receptor antagonists., Armishaw CJ, Daly NL, Nevin ST, Adams DJ, Craik DJ, Alewood PF, J Biol Chem. 2006 May 19;281(20):14136-43. Epub 2006 Feb 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16500898 16500898] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Armishaw, C | + | [[Category: Armishaw, C J.]] |
[[Category: diselenide bond]] | [[Category: diselenide bond]] | ||
[[Category: disulfide bond]] | [[Category: disulfide bond]] | ||
[[Category: helix]] | [[Category: helix]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:36:14 2008'' |
Revision as of 14:36, 21 February 2008
|
Solution structure of [Sec2,8]-ImI
Overview
Disulfide bonds are important structural motifs that play an essential role in maintaining the conformational stability of many bioactive peptides. Of particular importance are the conotoxins, which selectively target a wide range of ion channels that are implicated in numerous disease states. Despite the enormous potential of conotoxins as therapeutics, their multiple disulfide bond frameworks are inherently unstable under reducing conditions. Reduction or scrambling by thiol-containing molecules such as glutathione or serum albumin in intracellular or extracellular environments such as blood plasma can decrease their effectiveness as drugs. To address this issue, we describe a new class of selenoconotoxins where cysteine residues are replaced by selenocysteine to form isosteric and nonreducible diselenide bonds. Three isoforms of alpha-conotoxin ImI were synthesized by t-butoxycarbonyl chemistry with systematic replacement of one ([Sec(2,8)]ImI or [Sec(3,12)]ImI), or both ([Sec(2,3,8,12)]ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the alpha7 nicotinic acetylcholine receptor, with each selenoanalogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.
About this Structure
2BC7 is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
Reference
Alpha-selenoconotoxins, a new class of potent alpha7 neuronal nicotinic receptor antagonists., Armishaw CJ, Daly NL, Nevin ST, Adams DJ, Craik DJ, Alewood PF, J Biol Chem. 2006 May 19;281(20):14136-43. Epub 2006 Feb 24. PMID:16500898
Page seeded by OCA on Thu Feb 21 16:36:14 2008
