Ryan McGuinness, Christopher B. Tom, and Joshua S. Salafsky
Changes in conformation underlie the fundamental function of all proteins. Innovative therapeutics such as Gleevec function by holding its target protein in a non-active conformation that is unique across the kinome. Direct detection of protein conformational change offers a significant opportunity for the design of structurally-specific therapeutics. We have adapted Second Harmonic Generation (SHG), an optical technique to a discovery format to detect conformational change in a series of protein standards which represent a range of movement (rigid to floppy.) We will describe our use of SHG to screen and identify inhibitors of spermine-induced conformation change in monomeric alpha-synuclein, a key protein implicated in the etiology of Parkinson’s disease. In addition, we will introduce SHG as a means of uniquely identifying conformation-specific changes in kinases.
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