1rwp

From Proteopedia

Revision as of 17:01, 12 November 2007

Crystal structure of human caspase-1 in complex with 3-{6-[(8-hydroxy-quinoline-2-carbonyl)-amino]-2-thiophen-2-yl-hexanoylamino}-4-oxo-butyric acid

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.

About this Structure

1RWP is a Protein complex structure of sequences from Homo sapiens with HQC as ligand. Active as Caspase-1, with EC number 3.4.22.36 Full crystallographic information is available from 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:16511067

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