1nms: Difference between revisions

Revision as of 15:07, 21 February 2008

Caspase-3 tethered to irreversible inhibitor

OverviewOverview

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 StructureAbout this Structure

1NMS is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

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

Page seeded by OCA on Thu Feb 21 14:07:47 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 '''Caspase-3 tethered to irreversible inhibitor'''<br />
 ==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.
+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==
-NMS 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 161 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NMS OCA].
+NMS 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].
 ==Reference==
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 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Brian, T.O.]]
+[[Category: Brian, T O.]]
-[[Category: Choong, I.C.]]
+[[Category: Choong, I C.]]
-[[Category: DeLano, W.L.]]
+[[Category: DeLano, W L.]]
-[[Category: Erlanson, D.A.]]
+[[Category: Erlanson, D A.]]
-[[Category: Flanagan, W.M.]]
+[[Category: Flanagan, W M.]]
 [[Category: Lam, J.]]
 [[Category: Lee, D.]]
-[[Category: Luong, T.N.]]
+[[Category: Luong, T N.]]
-[[Category: Simmons, R.L.]]
+[[Category: Simmons, R L.]]
 [[Category: Wiesmann, C.]]
 [[Category: 161]]
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 [[Category: tether]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:22:54 2007''
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