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| [[Image:1rwm.gif|left|200px]] | | {{Seed}} |
| | [[Image:1rwm.png|left|200px]] |
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| {{STRUCTURE_1rwm| PDB=1rwm | SCENE= }} | | {{STRUCTURE_1rwm| PDB=1rwm | SCENE= }} |
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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'''
| | ===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=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16511067}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16511067 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16511067}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Waal, N D.]] | | [[Category: Waal, N D.]] |
| [[Category: Protein-small molecule inhibitor complex]] | | [[Category: Protein-small molecule inhibitor complex]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:59:34 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 14:30:21 2008'' |