Christopher French

===CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TETRAPEPTIDE INHIBITOR ACE-IETD-ALDEHYDE===

Caspase 8 is a member of the caspase family, a family of cysteine proteases that play an important role in inflammation and apoptosis or programmed cell death. The caspases are essential for apoptosis in cells during development and during later stages of life. Failure of apoptosis can lead to tumor formation and the development of autoimmune diseases. In addition, excess apoptosis has been implicated in various disease states, including ischemia and Alzheimer’s. Caspase 8 is just one of 11 caspases that have been indentified in humans. Caspase 8 is an “initiator caspase” which cleave inactive pro-forms of the effectors caspases and subsequently activating them. Caspases exist as inactive proenzymes that are composed of a prodomain, and a large and small protease subunit. The activation of caspase requires proteolysis at an internal aspartic residue which results in the generation of a heterodimeric enzyme with a large and small subunit. [[Image:Apoptosiscascade.jpg]]

Caspase 8 is a 58 kilodalton protein that shares similarities with other members of the caspase family. The protein is composed of two subunits, referred to as p18 and p11. These two subunits form a heterodimer. The protein has a α/ß folding motif that has a central six stranded beta sheet. Five of the strands are parallel and one is anti-parallel. The antiparallel strand is on the edge of the ß sheet. There are also six alpha helices in the protein structure. Three of these alpha helices are located on one side of the ß sheet and the other two on the other side. There is a turn of helix (α1’) which is part of a large loop (loop 1). This is along the binding pocket region of the p18 subunit. There is a two-stranded antiparallel ß sheet found at the top of the main ß sheet which forms the base of the binding pocket.  

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