1nme
From Proteopedia
(New page: 200px<br /> <applet load="1nme" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nme, resolution 1.60Å" /> '''Structure of Casp-3...) |
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| - | [[Image:1nme.gif|left|200px]]<br /> | + | [[Image:1nme.gif|left|200px]]<br /><applet load="1nme" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1nme" size=" | + | |
caption="1nme, resolution 1.60Å" /> | caption="1nme, resolution 1.60Å" /> | ||
'''Structure of Casp-3 with tethered salicylate'''<br /> | '''Structure of Casp-3 with tethered salicylate'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a | + | Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells. |
==About this Structure== | ==About this Structure== | ||
| - | 1NME is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 158 and 159 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1NME is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=158:'>158</scene> and <scene name='pdbligand=159:'>159</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NME OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Brian, T | + | [[Category: Brian, T O.]] |
| - | [[Category: Choong, I | + | [[Category: Choong, I C.]] |
[[Category: DeLano, W.]] | [[Category: DeLano, W.]] | ||
| - | [[Category: Erlanson, D | + | [[Category: Erlanson, D A.]] |
[[Category: Flanagan, M.]] | [[Category: Flanagan, M.]] | ||
[[Category: Lam, J.]] | [[Category: Lam, J.]] | ||
[[Category: Lee, D.]] | [[Category: Lee, D.]] | ||
| - | [[Category: Luong, T | + | [[Category: Luong, T N.]] |
[[Category: Simmons, B.]] | [[Category: Simmons, B.]] | ||
[[Category: Wiesmann, C.]] | [[Category: Wiesmann, C.]] | ||
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[[Category: cysteine proteinase; sulfonamide inhibition]] | [[Category: cysteine proteinase; sulfonamide inhibition]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:07:37 2008'' |
Revision as of 12:07, 21 February 2008
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Structure of Casp-3 with tethered salicylate
Overview
Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
About this Structure
1NME is a Protein complex structure of sequences from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
In situ assembly of enzyme inhibitors using extended tethering., Erlanson DA, Lam JW, Wiesmann C, Luong TN, Simmons RL, DeLano WL, Choong IC, Burdett MT, Flanagan WM, Lee D, Gordon EM, O'Brien T, Nat Biotechnol. 2003 Mar;21(3):308-14. Epub 2003 Feb 3. PMID:12563278
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