1rwm: Difference between revisions

Revision as of 15:55, 21 February 2008

Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid

OverviewOverview

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 StructureAbout this Structure

1RWM is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Caspase-1, with EC number 3.4.22.36 Full crystallographic information is available from OCA.

ReferenceReference

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:16511067

Page seeded by OCA on Thu Feb 21 14:55:23 2008

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OCA

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 '''Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-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==
-RWM 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 Q2Y 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=1RWM OCA].
+RWM 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=Q2Y:'>Q2Y</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=1RWM 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: Romanowski, M.J.]]
+[[Category: Romanowski, M J.]]
-[[Category: Waal, N.D.]]
+[[Category: Waal, N D.]]
 [[Category: Q2Y]]
 [[Category: protein-small molecule inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:07:39 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:23 2008''