1rwm
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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
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 Q2Y 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 Crystallograph Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:16511067
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