1rwk: Difference between revisions

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[[Image:1rwk.gif|left|200px]]<br />

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

<applet load="1rwk" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1rwk, resolution 2.30Å" />

'''Crystal structure of human caspase-1 in complex with 3-(2-mercapto-acetylamino)-4-oxo-pentanoic acid'''<br />

==Overview==

Caspase-1 is a key endopeptidase responsible for the post-translational, processing of the IL-1beta and IL-18 cytokines and small-molecule, inhibitors that modulate the activity of this enzyme are predicted to be, important therapeutic treatments for many inflammatory diseases. A, fragment-assembly approach, accompanied by structural analysis, was, employed to generate caspase-1 inhibitors. With the aid of Tethering with, extenders (small molecules that bind to the active-site cysteine and, contain a free thiol), two novel fragments that bound to the active site, and made a disulfide bond with the extender were identified by mass, spectrometry. Direct linking of each fragment to the extender generated, submicromolar reversible inhibitors that significantly reduced secretion, of IL-1beta but not IL-6 from human peripheral blood mononuclear cells., Thus, Tethering with extenders facilitated rapid identification and, synthesis of caspase-1 inhibitors with cell-based activity and subsequent, structural analyses provided insights into the enzyme's ability to, accommodate different inhibitor-binding modes in the active site.

Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.

==About this Structure==

1RWK 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 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1RWK OCA].

1RWK 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> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RWK OCA].

==Reference==

Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta ~~Crystallograph~~ Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067]

Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067]

[[Category: Caspase-1]]

[[Category: Homo sapiens]]

[[Category: Protein complex]]

[[Category: Brien, T.O.]]

[[Category: Brien, T O.]]

[[Category: Fahr, B.T.]]

[[Category: Fahr, B T.]]

[[Category: Lam, J.W.]]

[[Category: Lam, J W.]]

[[Category: Romanowski, M.J.]]

[[Category: Romanowski, M J.]]

[[Category: 158]]

[[Category: protein-small molecule inhibitor complex]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 19~~:07:~~36 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:17 2008''

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-[[Image:1rwk.gif|left|200px]]<br />
+[[Image:1rwk.gif|left|200px]]<br /><applet load="1rwk" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1rwk" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1rwk, resolution 2.30&Aring;" />
 '''Crystal structure of human caspase-1 in complex with 3-(2-mercapto-acetylamino)-4-oxo-pentanoic acid'''<br />
 ==Overview==
-Caspase-1 is a key endopeptidase responsible for the post-translational, processing of the IL-1beta and IL-18 cytokines and small-molecule, inhibitors that modulate the activity of this enzyme are predicted to be, important therapeutic treatments for many inflammatory diseases. A, fragment-assembly approach, accompanied by structural analysis, was, employed to generate caspase-1 inhibitors. With the aid of Tethering with, extenders (small molecules that bind to the active-site cysteine and, contain a free thiol), two novel fragments that bound to the active site, and made a disulfide bond with the extender were identified by mass, spectrometry. Direct linking of each fragment to the extender generated, submicromolar reversible inhibitors that significantly reduced secretion, of IL-1beta but not IL-6 from human peripheral blood mononuclear cells., Thus, Tethering with extenders facilitated rapid identification and, synthesis of caspase-1 inhibitors with cell-based activity and subsequent, structural analyses provided insights into the enzyme's ability to, accommodate different inhibitor-binding modes in the active site.
+Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.
 ==About this Structure==
-RWK 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 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1RWK OCA].
+RWK 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> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RWK OCA].
 ==Reference==
-Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta Crystallograph Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067]
+Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067]
 [[Category: Caspase-1]]
 [[Category: Homo sapiens]]
 [[Category: Protein complex]]
-[[Category: Brien, T.O.]]
+[[Category: Brien, T O.]]
-[[Category: Fahr, B.T.]]
+[[Category: Fahr, B T.]]
-[[Category: Lam, J.W.]]
+[[Category: Lam, J W.]]
-[[Category: Romanowski, M.J.]]
+[[Category: Romanowski, M J.]]
 [[Category: 158]]
 [[Category: protein-small molecule inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:07:36 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:17 2008''