1RWN

Crystal structure of human caspase-1 in complex with 3-{2-ethyl-6-[4-(quinoxalin-2-ylamino)-benzoylamino]-hexanoylamino}-4-oxo-butyric acid

Summary for 1RWN

• Entry DOI: 10.2210/pdb1rwn/pdb
• Related: 1bmq 1ibc 1ice 1rwk 1rwm 1rwo 1rwp 1rwv 1rww 1rwx
• Descriptor: Interleukin-1 beta convertase, 3-{2-ETHYL-6-[4-(QUINOXALIN-2-YLAMINO)-BENZOYLAMINO]-HEXANOYLAMINO}-4-OXO-BUTYRIC ACID, ... (4 entities in total)
• Functional Keywords: protein-small molecule inhibitor complex, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P29466 P29466
• Total number of polymer chains: 2
• Total formula weight: 30634.16

Authors

Romanowski, M.J.,Fahr, B.T.,O'Brien, T. (deposition date: 2003-12-16, release date: 2004-12-28, Last modification date: 2024-10-30)

Primary citation

O'Brien, T.,Fahr, B.T.,Sopko, M.M.,Lam, J.W.,Waal, N.D.,Raimundo, B.C.,Purkey, H.E.,Pham, P.,Romanowski, M.J.
Structural analysis of caspase-1 inhibitors derived from Tethering.
Acta Crystallogr.,Sect.F, 61:451-458, 2005

PubMed Abstract: 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.

PubMed: 16511067
DOI: 10.1107/S1744309105010109

Experimental method

X-RAY DIFFRACTION (2 Å)