Modulating caspase activity: beyond the active site.
Caspases are a family of aspartate-specific cysteine proteases that regulate cellular homeostasis through the mediation of apoptosis and inflammation. Despite keen interest in caspases as therapeutic targets for cancer, inflammatory, and neurodegenerative diseases, no active-site directed small molecule has yet succeeded in navigating human clinical trials. At the same time, recent biochemical and biophysical studies have revealed caspases to be highly dynamic proteases possessing a remarkable diversity of activation mechanisms. In addition, many caspases possess an allosteric circuit linking key active site loops with a distal allosteric site located at the dimer interface. Accordingly, small molecule binding at this allosteric site directly impacts structural organization of the active site and thus catalytic activity. Both cysteine-tethered and non-covalent reversible small molecules have recently been identified for these allosteric sites, with binding producing a variety of functional effects. Surprising new examples of caspase modulation have also been described recently, including a small molecule that binds caspase-6-substrate complexes uncompetitively and a short peptide that stabilizes an inactive, tetrameric form of procaspase-6. The confluence of recent biochemical, biophysical and pharmacological data has revealed exciting new avenues for the modulation of caspase activity via binding beyond the active site.
Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Jeremy
J
Murray
Adam R
AR
Renslo
D000595:Amino Acid Sequence; D000818:Animals; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D006801:Humans; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology
D054852:Small Molecule Libraries; D020169:Caspases