title: A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases.
abstract: One of the most promising and as yet underutilized means of regulating protein function is exploitation of allosteric sites. All caspases catalyze the same overall reaction, but they perform different biological roles and are differentially regulated. It is our hypothesis that many allosteric sites exist on various caspases and that understanding both the distinct and overlapping mechanisms by which each caspase can be allosterically controlled should ultimately enable caspase-specific inhibition. Here we describe the ongoing work and methods for compiling a comprehensive map of apoptotic caspase allostery. Central to this approach are the use of (i) the embedded record of naturally evolved allosteric sites that are sensitive to zinc-mediated inhibition, phosphorylation, and other posttranslational modifications, (ii) structural and mutagenic approaches, and (iii) novel binding sites identified by both rationally-designed and screening-derived small-molecule inhibitors.
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Kevin
authors: K
authors: Dagbay
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Scott J
authors: SJ
authors: Eron
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Banyuhay P
authors: BP
authors: Serrano
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Elih M
authors: EM
authors: Velázquez-Delgado
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Yunlong
authors: Y
authors: Zhao
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Di
authors: D
authors: Lin
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA.
authors: Sravanti
authors: S
authors: Vaidya
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts, USA. Electronic address: hardy@chem.umass.edu.
authors: Jeanne A
authors: JA
authors: Hardy
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D061945:Caspase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020169:Caspases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
chemical_list: D061945:Caspase Inhibitors; D020169:Caspases
keywords: Allostery; Anomalous X-ray diffraction; Apoptosis; Caspase; Chemical ligands; Conformational change; Cysteine protease; Exosite; Inductively coupled plasma; Phosphorylation; Zinc