1nms: Difference between revisions

[[Image:1nms.gif|left|200px]]<br /><applet load="1nms" size="350" color="white" frame="true" align="right" spinBox="true"  

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.

1NMS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=161:'>161</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NMS OCA].  

[[Category: Brian, T O.]]

[[Category: Choong, I C.]]

[[Category: DeLano, W L.]]

[[Category: Erlanson, D A.]]

[[Category: Flanagan, W M.]]

[[Category: Luong, T N.]]

[[Category: Simmons, R L.]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:07:47 2008''